Cancer Foye's Principles of Medicinal Chemistry-1219-1286

Chapter
37
Cancer and Chemotherapy
V I C T O R I A F. R O C H E
Drugs Covered in This Chapter

DNA cross-linking agents Pralatrexate Mitomycin
Miscellaneous DNA alkylating agents DNA methyltransferase inhibitors Miscellaneous anticancer agents
Altretamine Azacitidine Arsenic trioxide
Busulfan Decitabine Bortezomib
Nitrogen mustards Nelarabine
Mitosis inhibitors
Bendamustine DNA polymerase inhibitors
Cladribine Cabazitaxel
Chlorambucil
Clofarabine Docetaxel
Cyclophosphamide
Cytarabine Estramustine
Ifosfamide
Fludarabine Ixabepilone
Mechlorethamine
Gemcitabine Paclitaxel
Melphalan
Miscellaneous antimetabolites Vinblastine
Thiotepa
Hydroxyurea Vincristine
Nitrosoureas
Pentostatin Vinorelbine
Carmustine
Lomustine Pyrimidine antagonists Topoisomerase poisons
Streptozocin Capecitabine Daunorubicin
Organoplatinum complexes Floxuridine Doxorubicin
Carboplatin Fluorouracil Epirubicin
Cisplatin Purine antagonists Etoposide
Oxaliplatin Mercaptopurine Idarubicin
Picoplatin Thioguanine Irinotecan
Satraplatin Histone deacetylase inhibitors Mitoxantrone
Procarbazine and triazenes Romidepsin Teniposide
Dacarbazine Vorinostat Topotecan
Procarbazine Immunomodulators Valrubicin
Temozolomide Tyrosine kinase and related
Lenalidomide
Antimetabolites inhibitors
Thalidomide
Antifolates Dasatinib
Miscellaneous antibiotics Erlotinib
Methotrexate
Bleomycin Everolimus
Pemetrexed
Dactinomycin
1199
Lemke_Chap37.indd 1199 12/20/2011 2:24:50 PM

1200 PART III / PHARMACODYNAMIC AGENTS
Gefitinib Nilotinib Temsirolimus

Imatinib Sorafenib
Lapatinib Sunitinib
Abbreviations
ABC, ATP-binding cassette GAR, glycine amide ribonucleotide PDGFR, platelet-derived growth factor
ABL, Abelson GI, gastrointestinal receptor
AIC, 5-aminoimidazole-4-carboxamide GIST, gastrointestinal stromal tumors P-gp, P-glycoprotein
Ala, alanine GMP, guanosine monophosphate Ph, Philadelphia chromosome
AMP, adenosine monophosphate GSH, glutathione Phe, phenylalanine
APL, acute promyelocytic leukemia HER2, human epidermal growth factor Pt, platinum
Asn, asparagine receptor 2 RCC, renal cell carcinoma
Asp, aspartate HGPRT, hypoxanthine guanine ROS, reactive oxygen species
ATP, adenosine triphosphate phosphoribosyl transferase SNP, single nucleotide polymorphism
BCR, breakpoint cluster His, histidine SPF, sun protection factor
BCRP, breast cancer resistance protein hTS, human thymidylate synthase STEPS, System for Thalidomide
CLL, chronic lymphocytic leukemia Ile, isoleucine Education and Prescribing Safety
CML, chronic myelogenous leukemia ITPA, inositol triphosphate TEPA, triethylenephosphoramide
CNS, central nervous system pyrophosphatase THF, tetrahydrofolate
CYP, cytochrome P450 Leu, leucine Thr, threonine
Cys, cysteine Lys, lysine TK, tyrosine kinase
DACH, diaminocyclohexane MAP, microtubule-associated protein TKI, tyrosine kinase inhibitor
DHF, dihydrofolate MDR, multidrug resistance TNM, tumor-node-metastasis
DHFR, dihydrofolate reductase Met, methionine TopI, topoisomerase I
DPD, dihydropyrimidine dehydrogenase MMR, mismatch repair TopII, topoisomerase II
dTMP, deoxythymidine monophosphate MoAb, monoclonal antibody TPMT, thiopurine methyl transferase
dUMP, deoxyuridine monophosphate MTIC, 3-methyl-(triazen-l-yl) Trp, tryptophan
EGCG, epigallocatechin-3-gallate imidazole-4-carboxamide Tyr, tyrosine
EGFR, epidermal growth factor receptor mTOR, mammalian target of rapamycin Val, valine
FDA, U.S. Food and Drug NER, nucleotide-excision repair protein VEGFR, vascular endothelial growth
Administration NHL, non-Hodgkin lymphoma factor receptor
FPGS, folyl polyglutamate synthase
SCENARIO
Kelly Nystrom, PharmD, BCOP
DT, a 37-year-old white man, was diagnosed with precursor with ibuprofen 800 mg orally every 6 hours as needed) and left
B-cell acute lymphoblastic leukemia approximately 1 year ago. upper quadrant pain. A workup showed disease relapse and DL
He was treated with a R-Hyper-CVAD program (cyclophospha- was admitted for cycle 2 of re-induction with a R-Hyper-CVAD
mide, mesna, vincristine, doxorubicin and dexamethasone program.
alternating with rituximab, high-dose methotrexate and cytara-
bine) and achieved a complete remission. He presented to the (The reader is directed to the clinical solution and chemical analy-
office 1 month ago with complaint of mild headaches (treated sis of this case at the end of the chapter.)
INTRODUCTION programmed cell death (apoptosis). In cancer, these

regulatory processes have gone awry, and cells grow and
Healthy cells are under strict biochemical control for
growth and differentiation. Cells divide and prolifer- divide uncontrollably, consuming energy and losing both
ate under the influence of various growth stimulators structure and function due to an inability to adequately
and are subject to arrested growth (senescence) and differentiate. To add insult to injury, rampant cell division

CHAPTER 37 / CANCER AND CHEMOTHERAPY 1201
is accompanied by disabled cell-death processes, leading TABLE 37.1 Oncogenic Origin of Selected Cancers
first to cellular immortality and, eventually, to genetic
instability. The causes of cancer are many and varied Cancer Type Common Oncogenic or Tumor
(e.g., chemical, environmental, viral, and mutagenic), Suppressor Gene Origin
but all ultimately lead to an aberration in the expression Chronic myelogenous bcr-abl proto-oncogene
of proto-oncogenes, the products of which control nor- leukemia translocation
mal cell life. When these genes mutate to become onco-
genes in a sequential, multistep process, cancer results. Follicular lymphoma bcl-2 amplification, myc mutation
Oncogenes (e.g., myc and ras) can either overexpress or Sporadic thyroid cancer ret mutation
underexpress regulatory biochemicals, resulting in pref-
erential and accelerated cellular growth. Concomitantly, Colorectal and gastric cancer APC gene mutation
tumor suppressor genes (e.g., anti-oncogenes like p53, Familial breast and ovarian BRCA1, BRCA2 mutation
p21, pINK4A, and retinoblastoma) can be inhibited (1). cancer
Initially, tumors grow exponentially, taking a consistent
amount of time for every doubling of the tumor cell pop- Invasive ductal breast cancer HER2 amplification
ulation. In fact, the majority of a cancer cells lifetime is Familial melanoma p16INK4A mutation
spent before the tumor presents clinically. Initially, growth
is very rapid (doubling time measured in days), but dou- Childhood neuroblastoma, N-myc amplification
bling time can slow to weeks or months as the tumor ages small cell lung cancer
due to increasingly poor vascularization and the resulting Leukemia, breast, colon, c-MYC amplification
decrease in access to blood and essential nutrients (2). gastric, and lung cancer
Renal cell cancer VHL dysfunction
SELECTED DEFINITIONS
Oncogenes and Tumor Suppressor Genes Cell Cycle
Oncogenes are regulators of cellular communication When cells reproduce, they do so via a very specific game
with the outside environment. They are derived through plan known as the cell cycle. Cell division (mitosis) kicks
the mutation of proto-oncogenes, which are normal and off the cycle, and after a period of 30 to 60 minutes, the
ubiquitous genes involved in the regulation of homeo- cells go into either a resting phase (called G0) or a pre-
static cellular functions. Mutations in proto-oncogenes synthetic (gap) phase (called G1), in which enzyme pro-
can occur as spontaneous point mutations, inherited duction occurs in preparation for de novo nucleic acid
germline mutations, chromosomal rearrangements or synthesis. Production of DNA then occurs in an S phase
through augmentation of gene expression. Regardless that can last up to 20 hours. The S phase is followed by
of the mutational mechanism, when the mutated onco- a gap phase (G2), in which RNA, critical proteins, and
genes are stimulated by exposure to chemical, environ- the mitotic spindle apparatus are generated for the next
mental, or viral carcinogens, they produce proteins that mitotic (M) phase (3,4).
are either wrongly expressed within their normal cell or This is important to our discussion since some anti-
expressed in inappropriate tissues. In either case, cellular cancer agents are specific for a certain phase of the cell
proliferation leading to cancer results (1,3). cycle. For example, antimetabolite antineoplastics dam-
Tumor suppressor genes are intended to keep onco- age cells in the S phase, whereas mitosis inhibitors pack
genes in check by halting uncontrolled cellular growth. their greatest cell-killing punch in the M phase. The
In direct opposition to oncogenes, which induce cancer administration of cell cycle phase-specific antineoplas-
when stimulated or amplified, tumor suppressor genes tics is carefully planned so that the drug encounters can-
promote cancer when inactivated or attenuated. Two cer cells at their most vulnerable moments. This often
of the most prevalent tumor suppressor genes involved involves continuous infusion therapy or treatments
in the generation of cancer are p53 and retinoblastoma, spread over several days. Other antineoplastic agents are
or Rb. When either of these two suppressor genes loses toxic to cells regardless of cycle phase (e.g., DNA alkyl-
function, the negative control on cellular proliferation is ating agents and most antineoplastic antibiotics). These
lifted and cells gain immortality (an essential quality of a cell cycle phase-nonspecific agents can often be adminis-
cancer cell). The loss or disruption of function of the p53 tered as a single bolus injection and/or at any time that is
tumor suppressor gene is found in approximately half of feasible for the provider and convenient for the patient.
human cancers and is a harbinger of a poor prognosis. In general, cancer cells undergoing rapid division are
Oncogenes and tumor suppressor genes that have most vulnerable to the cytotoxic action of antineoplastic
been linked to specific types of cancer are identified in agents, and antineoplastic therapy holds its greatest prom-
Table 37.1 (1,3). Table 37.2 relates oncogenic markers ise for positive outcomes if initiated when the tumor is
of selected cancers to disease prognosis and treatment small but growing aggressively. Conversely, slow-growing
strategy (1). tumors with a high percentage of cells remaining in the

CLINICAL SIGNIFICANCE
Chemotherapy has significantly phophoramide mustard, but also produces acrolein, an elec-
changed the treatment of cancer trophilic aldehyde, which can cause significant damage to the
since the first agents were studied bladder by forming covalent bonds with cysteine residues of
in the 1940s. Understanding the chemi- essential proteins. This bladder damage, or hemorrhagic cystitis,
cal mechanism of action for traditional can be prevented with the use of mesna, a sulfhydryl-containing
chemotherapy agents, including whether the agent is cell-cycle cysteine decoy that inactivates the effects of acrolein in the blad-
specific or cell-cycle nonspecific, is important so administration der. In addition, deficiencies found in individual patients can
can be planned accordingly and co-administration of agents with impact toxicities of certain chemotherapy agents.
similar toxicities can be avoided. Dihydropyrimidine dehydrogenase (DPD) is needed to deac-
The disadvantage of traditional chemotherapy agents is tivate both fluorouracil and capecitabine, which is a prodrug
the inability of the agent to recognize the difference between of fluorouracil. About 5% of the population has a deficiency
normal and cancer cells. So, although the agents may shrink of DPD, which results in accumulation of the drug and leads to
or eliminate the tumor, the treatment is accompanied by many severe toxicity if fluorouracil or capecitabine are administered.
unwanted side effects. There are numerous examples where the Recognizing the metabolic profile of these agents allows phar-
chemical understanding of the chemotherapy agent is neces- macists to identify pharmacogenetically at-risk patients so that
sary. For example, when an anthracycline, such as doxorubicin, the safest dose of these highly toxic drugs can be administered.
is given, free radicals are formed through an iron-dependent pro- Understanding the chemical basis for the toxicities seen
cess that begins with the reduction of the anthracycline quinone with chemotherapy is imperative in managing or preventing
ring to a hydroquinone. These free radicals can cause significant them in clinical practice.
cardiac damage if left unmonitored. Dexrazoxane is a product
that is predictably hydrolyzed to an electron-rich metabolite that Kelly Nystrom, Pharm.D., BCOP
binds to iron and prevents these toxic free radicals from being Associate Professor
formed, thus reducing damage to the heart. Another example Pharmacy Practice Department
can be found when using cyclophosphamide or ifosfamide. The School of Pharmacy and Health Professions
dissociation of aldophosphamide produces the active compound Creighton University
G0 phase (e.g., non-small cell lung cancer) are often non- they can put down roots and evolve into a full-fledged
responsive to cell cycle-specific chemotherapy (4). If the metastatic tumor. Since many distinct and interdepen-
tumor is not detected until it is quite large, therapy can dent steps must be accomplished to establish metastatic
also be compromised by inefficient or substandard drug disease, the process has been termed the metastatic
delivery due to poor tumor vascularization. cascade (5). Fortunately, there are many opportunities
within the cascade for the body to mount a successful
Metastasis defense and destroy the potential invaders.
Metastasis refers to the process by which malignant cells
leave the parent tumor, migrate to distant sites, and Cancer Staging
invade new tissue. The primary metastatic highways used Clinicians need to have a common language through
by meandering cancer cells are the blood and lymph which to communicate about disease severity to make the
fluids. Sloughed cells must find a biologic environment best team-based decisions about the relative risks and ben-
with all of their essential growth factors in place before efits of treatment options. In the tumor-node-metastasis
TABLE 37.2 Oncogenic Markers and Therapeutic Strategies in Selected Cancers

Cancer Type Oncogenic Marker Prognosis/Responsiveness Approach
to Chemotherapy
Breast cancer HER2 amplification Poor Aggressive chemotherapy,

targeted therapy
Acute myelogenous t(8;21) or inv(16) Good Standard chemotherapy

leukemia translocation
Acute lymphocytic leukemia bcr-abl rearrangement Poor Bone marrow transplantation

(TNM) cancer staging classification, the severity of solid relationship between resident genes and oncogenes,
tumor neoplastic growth is characterized by the size of Dr. Wogloms rather gloomy prognosis of our ability to
the tumor mass (T1 to T4), the extent of lymph node meet cancer on its own ground and beat it was under-
involvement (N0 to N3), and whether distant metastasis pinned by centuries of unsuccessful attempts to treat
has occurred (M0 or M1). The larger the subscripted neoplastic disease with toxic metals, including lead,
number in each of these parameters, the more advanced arsenic, silver, zinc, antimony, mercury, and bismuth.
and/or disseminated the disease. Taken together, the However, the era of more promising chemotherapy was
TNM characteristics of a tumor can be translated into a just on the horizon even as Woglom penned his words
comprehensive staging scale ranging from I (localized) of therapeutic woe.
to IV (metastatic). The intermediate disease severity Among the first nonmetallic therapeutic agents to
stages indicate local (stage II) or regional (stage III) tis- show benefit in the treatment of cancer was cortisone
sue invasion (3). Staging is an essential prerequisite for and, later, prednisone. In the 1940s, these glucocorti-
the prediction of prognosis and the identification of the coids were shown to induce tumor regression in a labo-
most appropriate treatment plan and optimal dosing ratory cancer model (murine lymphosarcoma) and in
regimen (2). acute leukemia. In the same decade, the retrospective
recognition that World War I soldiers exposed to sul-
Response Criteria fur mustard gas, used as an agent of war, suffered from
In this era of patient-centered, team-based care, it is damaged lymphoid tissue and bone marrow led to the
equally beneficial to quantify a patients clinical response development of the cytotoxic nitrogen mustards for the
to therapy in a manner that is consistent and universally treatment of lymphoma. Chemists then used their scien-
understood by all health care providers. Five discrete anti- tific understanding of mustard reactivity to design agents
cancer therapy response categories have been defined, that were either superpotent and nonselective (e.g.,
with criteria established for each (3). Whereas cure is obvi- highly toxic) or of lower reactivity so as to provide oral
ously the most noble goal, it is very difficult to achieve in activity and less systemic toxicity.
most types of cancer. A cure for all cancers except breast The discovery in 1940 that p-aminobenzenesulfon-
and melanoma equates to no evidence of disease for a amide was effective against streptococcal infections ush-
minimum of 5 years. More commonly, the response cat- ered in the era of antimetabolite chemotherapy. The
egory viewed as the pinnacle is complete response, in which development of antifolate antineoplastics, which were
the patient has no evidence of cancer for at least 1 month shown to be effective in combating childhood leuke-
following the cessation of therapy, but where relapses are mias, got its start in the late 1940s. In the mid to late
still possible. A partial response is claimed when tumor size 1950s, on the heels of the success of antifolates, came
has been reduced by 30% or more and there is no evi- the development of antimetabolites based on the struc-
dence of new lesions at the primary site or elsewhere for a tures of endogenous purine and pyrimidine bases.
minimum of 1 month. If this level of clinical improvement Perhaps the most exciting discovery in this regard was
is not reached, yet the patient has experienced significant the recognition that a very simple analog of the endog-
attenuation of symptoms and/or enhancement of quality enous pyrimidine uracil (5-fluorouracil) was a potent
of life, the response is termed clinical benefit. A less opti- inhibitor of deoxythymidine monophosphate biosynthe-
mistic response category is stable disease, in which tumor sis and that inhibiting the production of this essential
size has either increased by less than 20% or decreased by nucleotide produced positive results in patients suffer-
less than 30%. Most dire is progression, a category that is ing from colon, stomach, pancreatic, and breast cancers.
characterized by tumor growth at the 20% or higher level Antimetabolites that target DNA polymerase (e.g., cyta-
and/or the formation of new lesions during therapy. rabine) were conceptualized and synthesized in the late
1950s and subsequently shown to be effective in acute
myeloblastic leukemia.
HISTORICAL BACKGROUND (6) The antibiotic antineoplastics came into clinical util-
ity when the highly toxic actinomycin (discovered in
Those who have not been trained in chemistry or medicine, the 1940s) was found to be effective in the treatment of
which after all is only applied chemistry, may not realize how human testicular cancer and uterine choriocarcinoma.
difficult the problem of [cancer] treatment really is. It is
Other natural anticancer antibiotics, such as bleomycin,
almost, not quite, but almost as hard as finding some agent
subsequently were found to be active against various
that will dissolve away the left ear, say, yet leave the right ear
hematologic cancers and solid tumors (1960s), which
unharmed: so slight is the difference between the cancer
cell and its normal ancestor.
led in more recent times to the development of semisyn-
thetic analogs with both high potency and wider margins
Thus wrote noted cancer researcher and physician of safety. The antimitotic vinca alkaloids vincristine and
Dr. William H. Woglom in a monograph published vinblastine were shown to have activity against Hodgkins
by the American Association for the Advancement disease and acute lymphoblastic leukemia around the
of Science in 1947 (7). Although somewhat predic- same time that the antibiotic antineoplastics were being
tive of what we now know to be true regarding the developed.

Cancer chemotherapy appears to have come full circle chemists to conceptualize and visualize molecular interac-
since the metal-intense Renaissance, because some of tions between potential drugs and putative receptor targets
the newer anticancer drugs to join the U.S. market are that lead to rational drug design and development, as well
organometallic platinum (Pt) complexes. The activity of as in analyzing and managing the overwhelming amounts
cisplatin (the first such complex to be commercially avail- of data that are generated from these studies, cannot be
able) against lymphosarcoma and solid tumors of the overestimated. Likewise, the availability of viable tumor
head, neck, and reproductive organs was first noted in cell lines has facilitated a disease-specific orientation to
the early 1970s. The fortuitous discovery of organoplati- the hunt for more effective therapies. Currently, there are
num complexes in the treatment of cancer is attributed tumor cell lines for lung, colon, breast, ovarian, brain, and
to Dr. Barnett Rosenberg, who was studying the impact of kidney cancers, as well as for melanoma and leukemia (8).
electromagnetic radiation on bacterial cell growth using Several monoclonal antibodies targeted to tumor cell
platinum electrodes. He followed up on the astute obser- antigens or proteins critical to cellular proliferation (e.g.,
vation that the bacteria exposed to the electrodes expe- human epidermal growth factor, vascular endothelial
rienced profound changes in cellular structure, which growth factor, tyrosine kinase, and proteasomes) have
ultimately were attributed to the in situ generation of cis- found their way to the U.S. market. In addition, several
platin. Both Pt(II) and Pt(IV) analogs of cisplatin, which new targets for anticancer drug development currently
offer high potency coupled with lower resistance poten- are being actively explored by biomedical scientists (1,8).
tial and fewer use-limiting side effects (e.g., oto-, nephro-, For example, cancer cells overexpress the enzyme telom-
and hematotoxicity), are currently on the market and in erase, which inhibits the natural destruction of chromo-
clinical trials. In addition to organometallics, the efficacy somal telomeres (DNA caps), leading to unwanted cellular
of sex hormones and hormone antagonists in fighting immortality. Telomerase inhibitors would be expected to
hormone-dependent cancers (e.g., estrogen receptor reestablish cellular senescence and to halt uncontrolled
positive breast cancer or prostate cancer) and the advent cell division by maintaining the integrity of the telomeres
of therapeutic biologic response modifiers with direct and are being pursued as a new biochemical approach to
antiproliferative effects (e.g., interferons) have added disease attenuation or control (9). Other potential anti-
significantly to the therapeutic options available to pro- neoplastic drug targets being seriously investigated are
viders and the cancer patients for whom they care. aberrant genes or enzymes unique to specific tumors and
The later 1990s saw the introduction of the tyrosine P-glycoprotein (P-gp), which is overexpressed in many can-
kinase inhibitors (TKIs) to the antineoplastic arma- cers as a result of an amplified mdr-1 gene and responsible
mentarium. The recognition in 1960 that a mutant for the rapid ejection of antineoplastic agents from target
chromosome known as BCR-ABL (or the Philadelphia cells. Other multidrug resistanceassociated proteins (the
[Ph] chromosome) appeared consistently in the cells MRP family) involved in this devastating rebound of the
of patients with chronic myelogenous leukemia (CML) cancer cell are also being investigated as potential sites of
represented the first time a chromosomal aberration had therapeutic intervention. The intense focus on resistance
been directly linked to a neoplastic disorder. The prod- molecules such P-gp is warranted because patients whose
uct of this abbreviated chromosome, the Bcr-Abl protein, tumors express this efflux-promoting protein respond
is an unregulated tyrosine kinase that promotes cellular poorly to chemotherapy and have a poor prognosis (2).
proliferation at the expense of apoptosis. Imatinib, the It is hoped that clinicians will one day be able to gen-
first rationally designed drug in the TKI class, was made erate a genetic expression profile for each patient to
available in 2001 and dramatically changed the treatment help them assess the likelihood of response to all pos-
and clinical outcome of Ph-positive leukemias. Although sible therapies and to guide pharmacotherapy selection.
imatinib selectively targets the Bcr-Abl protein, other Pharmacogenomics-based predictors of therapeutic
inhibitors with selectivity for epidermal growth factor response to anticancer drugs currently being explored
receptor (EGFR) and vascular endothelial growth factor include single nucleotide polymorphisms (SNPs) and
receptor (VEGFR) kinases soon followed. These growth the multiplicity of genes and gene products within a sin-
factorselective TKIs show efficacy in the treatment of gle biochemical pathway (10). While there are multiple
solid tumors of the lung, breast, pancreas, and kidney. scientific, regulatory, and ethical barriers to overcome
Despite the wide range of antineoplastic agents cur- before the full power of pharmacogenomics can posi-
rently available, it has been estimated that approximately tively impact the care of every cancer patient, these issues
40% of patients with cancer ultimately succumb to their are being actively addressed at the national level, giving
disease (3). Novel therapies based on an in-depth under- hope that the age of individualized cancer chemotherapy
standing of the molecular mechanisms involved in the may indeed be close at hand.
complex cascade of events we call cancer are urgently
needed. Fortunately, molecular targets for focused che-
motherapeutic interventions are being discovered with
DISEASE STATE
increasing regularity, opening the door for the scientifi- Cancers can usually be classified as lymphatic, epithelial,
cally grounded development of new drugs. The critical role nerve, or connective tissue related, and tumor nomen-
of computer-based technology in facilitating the ability of clature is based on tissue of origin as follows: carcinoma

(epithelial origin), sarcoma (muscle or connective tissue TABLE 37.4 The American Cancer Societys Major
origin), leukemia and lymphoma (lymphatic or hema- Warning Signs of Cancer
tologic origin), and glioma (neural origin). The risk of
developing epithelial-derived cancers increases with age. Cancer Warning Signs in Cancer Warning Signs in
Adults Children
Incidence Change in bowel or bladder Continued unexplained
In 2007, approximately 1.4 million people received a diag- habits weight loss
nosis of cancer, and approximately 560,000 died of the A sore that does not heal Frequent headaches, with
disease (3). The American Cancer Society estimates that vomiting
over 1.5 million new cases of cancer will be diagnosed in
2010 (11). If the ratio of new diagnoses to deaths observed Unusual bleeding Persistent pain in bones
or discharge or joints
in 2007 holds steady, over 555,000 lives will be lost. The
most commonly acquired cancers include those of the Thickening or lump in Any unusual mass
prostate, breast, lung, colon, and rectum. Lung cancer is breast or elsewhere or swelling
the most fatal and will be responsible for approximately Indigestion or difficulty Sudden eye or vision
157,000 U.S. deaths in 2010. These prominent cancers in swallowing changes
(prostate/breast, lung, and colorectal) occur with very
Obvious change in a wart Recurrent or unexplained
similar frequency in men and women, and few gender- or mole fever
related differences in mortality have been noted (Table
37.3) (11). Some geographical differences in incidence Nagging cough Excessive bruising
have been observed, with lung cancer being more preva- or hoarseness or bleeding
lent in rural southern U.S. states, and breast and colon Noticeable paleness or loss
cancer more commonly diagnosed in the northeast cor- of energy
ridor of the United States (12).
Signs and Symptoms

abandoned in favor of the multiple mutation prerequisite,
The clinical manifestations of cancer can vary widely and complex gene pathways, interactions, and communi-
depending on type and stage of neoplastic disease. The cations are now the focus of study in the understanding
American Cancer Society has been promulgating its list of malignant processes and their treatments. Once deter-
of the major warning signs of cancer for decades (Table mined, the mutational profile of malignant cells may
37.4) (3,13). Patients are well-served by being familiar very well predict such parameters as disease severity, most
with these early warning signs because cancer is most promising therapeutic interventions, and clinical outcome.
effectively treated when diagnosed before advanced dis- The development of cancer occurs in four discrete
ease develops. Recognizing that the first letters of each steps or phases. In the initiation phase, exposure to a
sign spell the word caution can help adults remember precipitating carcinogen prompts irreversible mutation
them. One readily recognized symptom of cancer is per- in a number of different genes. The promotion phase is
sistent weight loss (especially in children), and severe, a time during which mutated cells arising from altered
unrelenting pain is a hallmark symptom of cancer in the genes grow preferentially compared to normal cells. This
later stages. Solid tumors can become palpable or observ- preferential growth may result from continued exposure
able masses when the cancer is advanced. to the original carcinogen or from promotion by envi-
ronmental accelerants. This stage is reversible, so can-
Biochemical Bases and Causes of Cancer cer sometimes can be avoided with appropriate changes
Currently, it is understood that cancer is caused by muta- in diet and lifestyle. The transformation phase is the 5-
tions in resident or normal genes rather than by the to 20-year progression of a mutated cell to a cancer cell.
introduction of foreign genes into otherwise healthy sys- Cellular proliferation, clonal colony development, tissue
tems (1,3). The single-gene theory of cancer (where a sin- invasion and destruction, and metastasis define the final
gle mutation could result in neoplastic disease) has been progression phase of cancer development (3).
TABLE 37.3 Estimated 2010 U.S. Incidence and Mortality of Common Cancers
Prostate/Breast Lung and Bronchus Colorectal
Men Women Men Women Men Women
Incidence 217,730 (28%) 207,090 (28%) 116,750 (15%) 105,770 (14%) 72,090 (9%) 70,480 (10%)
Mortality 32,050 (11%) 39,840 (15%) 86,220 (29%) 71,080 (26%) 26,580 (9%) 24,790 (9%)

As previously mentioned, the genetic mutations lead- TABLE 37.6 Some Environmental Precipitants
ing to the diseases that we call cancer can be stimulated of Cancer
by a variety of chemical, environmental, and viral trig-
gers. Both RNA retroviruses and DNA viruses have been Environmental Cancer Cancer Type
implicated in human cancer causation (Table 37.5), Precipitant
although many more DNA than RNA viruses have onco- Tobacco Lung, oral, bladder, pancreatic,
genic potential (14,15). stomach, and renal cancer
Individuals in certain occupations may be at enhanced
risk for the development of some cancers due to unavoid- Alcohol Liver, rectal, and breast cancer
able exposure to carcinogenic chemicals (12). Perhaps Tobacco plus alcohol Oral cancers
the best-known example of occupationally induced can-
Radon Lung cancer
cer involves exposure to asbestos, which has been con-
clusively linked with the development of lung, pleural, Halogenated compounds Bladder cancer
and peritoneal malignancies. Miners exposed to radon
Immunosuppressive agents Lymphoma
are also at a significantly enhanced risk for the develop-
ment of lung cancer, as are individuals exposed through Herbicides Lymphoma
their work to soot, tars, hexavalent chromium, and
Ionizing or ultraviolet radiation Leukemia, breast, thyroid, lung,
nickel-containing compounds. The aromatic amines and skin cancer
-naphthylamine and 4-aminobiphenyl are known to
induce bladder cancer, and exposure to the common
organic solvent benzene has been linked to the develop-
ment of leukemia. moderation is a choice that individuals can make in an
Environmental carcinogens are all around us effort to decrease their overall risk of developing cancer.
(Table 37.6) (12). Fortunately, individuals can do many Other measures that patients can take to minimize the risk
things to protect themselves from exposure or from nega- of cancer from environmental causes include protection
tive consequences of limited exposure. The chemicals from damaging ultraviolet rays through the use of high-
deposited in the lungs from inhaling cigarette smoke are SPF (sun protection factor) sunscreens and the consump-
the primary cause of lung cancer in the United States, but tion of foods that are low in fat but rich in carotenoids,
smokers who quit decrease their risk for this often-fatal vitamins A and C, folate, selenium, and/or fiber (12).
cancer by 67% or more after 10 smoke-free years (12).
Nonsmokers can protect themselves from the cancer-
promoting effects of secondhand smoke by removing GENERAL THERAPEUTIC APPROACHES
themselves from smoke-filled environments. Smoking Cancer treatment can be comprised of surgery, radiation,
combined with alcohol has a synergistic effect in promot- antineoplastic chemotherapy, and/or therapy with bio-
ing the development of oral cancer. In addition to quit- logic response modifiers, which stimulate the patients
ting smoking, abstaining from alcohol or drinking in own immunologic defense mechanisms. Surgery and
radiation (ionizing, thermal, or photodynamic) are
favored for isolated or localized cancers; chemotherapy
and biologic response modifiers (with or without surgery
TABLE 37.5 RNA and DNA Viruses Associated with and/or radiation) are reserved for disseminated or sys-
Cancer Development temic cancers. Chemotherapy can also be used after sur-
Virus Cancer gery and/or radiation as an insurance policy against
microscopic metastatic disease (adjuvant therapy) or
RNA Virus before surgery to decrease the size of the mass to be
Human Adult T-cell leukemia removed (neoadjuvant therapy).
T-lymphotrophic virus Unfortunately, cancer cells do not simply lie down in
the face of chemotherapeutic intervention. Rather, these
Hepatitis C Hepatocellular carcinoma
aggressive cells fight back in an attempt to retain their
DNA Virus immortality. Some cancer cells acquire resistance to anti-
cancer drugs by downregulating enzymes essential for
Hepadnavirus Hepatocellular carcinoma
drug transport or for the activation of antineoplastic pro-
Papillomavirus Skin cancer, cervical cancer, anogenital drugs, or by upregulating enzymes involved in inactivating
cancer biotransformation. As noted previously, other mechanisms
Epstein-Barr virus Burkett lymphoma, Hodgkins disease,
of biochemical retaliation include downregulation of tar-
anaplastic nasopharyngeal carcinoma, get enzymes, altered drug uptake and efflux mechanisms
gastric cancer (e.g., amplification of the gene that encodes for P-gp or
the multidrug resistanceassociated protein), inhibition
Herpes Karposi sarcoma
of cellular repair proteins, and apoptosis inhibition (24).

Cancer Chemotherapy colony-stimulating factor, which boosts the ability of

The word antineoplastic means against new growth. In bone marrow to produce neutrophils, has had a positive
general, the mechanism of cytotoxic action for all anti- impact on optimizing dosing intensity/density.
neoplastic agents is interference with cellular synthesis or Finally, many chemotherapeutic agents produce seri-
the function of RNA, DNA, and the proteins that sustain ous chronic or delayed toxicities that may be irreversible,
life. All antineoplastic agents are poisons because they particularly in heart, lung, and kidneys, which demands
are designed to kill cells. Currently available anticancer that the total cumulative dose be taken into account
drugs are often highly and generally toxic, especially when designing the regimen. The ultimate balancing act
for cells with short half-lives. For example, nonspecific is to give the patient as much antineoplastic drug as is
destruction of the rapidly dividing cells of the gastroin- normally recommended in the time frame most likely to
testinal (GI) tract leads to the severe nausea and vom- kill the greatest percentage of cancer cells without induc-
iting associated with cancer chemotherapy, whereas ing intolerable or life-threatening toxicity in healthy
alopecia and fatigue (as well as susceptibility to infection) organs and tissues. Armed with the knowledge of the
are the result of the destruction of rapidly dividing cells biochemical and/or molecular basis of toxicity, the phar-
in hair follicles and bone marrow, respectively. Factors macist is in an excellent position to employ appropriate
such as the extent and severity of the disease, individual pharmacotherapeutic agents to attenuate unavoidable
sensitivity to the antineoplastic mechanism employed by side effects.
the drugs selected for use, the kinetics controlling drug One approach for minimizing unwanted toxicity is to
transport, and cell cycle specificity all impact the chance employ a chemotherapeutic regimen of several drugs
for chemotherapeutic success (2). that act by distinct mechanisms and/or precipitate dif-
Because cancer chemotherapy is most often given in ferent side effects. Attacking the tumor with different
several courses or rounds, with an interval of several therapeutic guns should target a larger variety of the
days or weeks in between to permit attenuation of side mutant cells that comprise the tumor and permit a lower
effects, three distinct aspects of drug dosing must be con- dose of each to be used compared to single-agent ther-
sidered when determining the impact of antineoplastic apy. Minimizing side effect overlap provides a greater
therapy on overall patient welfare. First, the dose that chance that the patient will be able to tolerate therapy
ideally should be given per course has been identified and accommodate a shorter interval between courses.
for each commonly employed antineoplastic agent but It is essential that the oncology pharmacist be well
can be altered significantly by individual patient health versed in the pharmacotherapy-based management of
status (e.g., hepatic, renal, cardiovascular, hematopoi- severe pain, infection, and the nausea, vomiting, and
etic, pulmonary, and/or other comorbidities), activity/ fatigue associated with chemotherapy. The provision of
performance status, genetic makeup, and the nature and contemporary and valid drug information to patients
anticipated severity of side effects. Each round of anti- and families is essential, as is assistance in helping with
neoplastic therapy kills a given percentage of cancer cells the interpretation of information that patients and loved
with each administration (cell kill hypothesis), and the ones secure either through their health care providers or
percentage killed rises proportionally with the dose of independently (e.g., from the Internet).
drug. If chemotherapy can shrink tumors to 104 or fewer
cells, normal host defense systems are usually capable of THERAPEUTIC CLASSES OF ANTICANCER
eradicating them (2,3). Therefore, the dose of drug that DRUGS
comes as close as possible to the recommended dose is the
goal. Expect significant interpatient variation in response DNA Cross-Linking Agents (Alkylators and
to the same chemotherapeutic regimen secondary to Organometallics)
individual genetics, level of debilitation, extent of tissue The primary target of DNA cross-linking agents is the
invasion, critical organ system function (including bone actively dividing DNA molecule. The DNA cross-linkers
marrow), and past exposure to chemotherapeutic agents. are all extremely reactive electrophilic (+) structures.
As alluded to earlier, an ever-growing understand- When encountered, the nucleophilic groups on various
ing of genetic polymorphism and its impact on the bio- DNA bases (particularly, but not exclusively, the N 7 of
synthesis of target proteins and metabolizing enzymes guanine) readily attack the electrophilic drug, resulting
is helping health care providers make wiser decisions in irreversible alkylation or complexation of the DNA
about antineoplastic therapy and drug regimens. The base.
length of the drug-free interval is the second important Some DNA alkylating agents, such as the nitrogen
drug-dosing consideration because a shorter interval (or mustards and nitrosoureas, are bifunctional, meaning
higher dose intensitythe one-two punch) is associ- that one molecule of the drug can bind two distinct DNA
ated with a more aggressive inhibition of tumor growth. bases. Most commonly, the alkylated bases are on differ-
Most often, patients cannot tolerate the debilitating side ent DNA molecules, and interstrand DNA cross-linking
effects (e.g., myelosuppression) without a prolonged through two guanine N7 atoms results. The DNA alkylat-
interval between rounds. The advent of genetically engi- ing antineoplastics are not cell cycle specific, but they are
neered biologic response modifiers, such as granulocyte more toxic to cells in the late G1 or S phases of the cycle.

This is the time when DNA is unwinding and exposing its R

nucleotides, increasing the chance that vulnerable DNA Cl CH2 CH2 N CH2 CH2 Cl
functional groups will encounter the electrophilic anti-

Bis--haloalkylamine
neoplastic drug and launch the nucleophilic attack that
leads to its own destruction. The DNA alkylators have a
great capacity for inducing both mutagenesis and carci- MECHANISM OF ACTION The mechanism of action of the
nogenesis; in other words, they can promote cancer in nitrogen mustards (16) is depicted in Figure 37.1. In
addition to treating it. step 1, the lone pair of electrons on the unionized amino
Organometallic antineoplastics (platinum coordina- group conducts an intramolecular nucleophilic attack at
tion complexes) also cross-link DNA, and many do so by the -carbon of the mustard, displacing chloride anion
binding to adjacent guanine nucleotides, called diguano- and forming the highly electrophilic aziridinium ion
sine dinucleotides, on a single strand of DNA. This leads intermediate, a quaternary amine. The carbon atoms of
to intrastrand DNA cross-linking. The anionic phosphate this strained cyclic structure are highly electrophilic due
group on a second strand of DNA stabilizes the drug to the strong negative inductive effect of the positively
DNA complex and makes the damage to DNA replication charged nitrogen atom.
irreversible. Some organometallic agents also damage In step 2, a DNA nucleophile conducts an intermolec-
DNA through interstrand cross-linking. ular nucleophilic attack, which breaks the aziridine ring
and alkylates DNA. Although guanine is the preferred
nucleic acid base involved in the alkylation reaction,
Nitrogen Mustards and Aziridine-Mediated Alkylators adenine is also known to react. Of critical importance is
Nitrogen mustards are bis(-haloalkyl)amines. The the fact that the lone pair of electrons on the mustard
term bis means two, and the halo (short for halo- nitrogen is regenerated when the aziridine ring cleaves.
gen) in the nomenclature is invariably chlorine. The Steps 3 and 4 are simply repetitions of steps 1 and 2,
two chlorine atoms dramatically decrease the basic respectively, involving the second arm of the mustard and
strength of the amino nitrogen through a strong nega- a second molecule of DNA. Ultimately, two molecules of
tive inductive effect. As a result, the unionized conju- DNA will be cross-linked through the carbon atoms of
gate of these drugs predominates at physiologic pH. what was once the nitrogen mustard. Finally, hydrolytic
This is intentional because it is the unionized amine depurination (step 5) cleaves the bound guanine resi-
(with its lone pair of electrons) that allows the forma- dues from the DNA strand. This is an attempt to liberate
tion of the highly electrophilic aziridinium ion, which is the DNA from the mustards covalent stranglehold, but
the reactive DNA-destroying intermediate generated by the DNA released from this mustard trap is damaged and
all true mustards. unable to replicate. Cell death is the inevitable result. If
Cl
R Cl
Step 2: Intermolecular attack R Cl
Step 1: R
Cl CH2 CH2 N CH2 CH2 Cl N N
Intramolecular O Cl guanine DNA
nucleophilic attack
+ + N NH
Bis(-haloalkyl)amine Aziridinium ion N N NH2 Alkylated DNA
deoxyribose-5'-phosphate-DNA
Step 3: Intramolecular
nucleophilic attack
Cl Cl
Step 4: Intermolecular attack Cl Cl
R R
DNA-guanine CH2 CH2 N CH2 CH2 guanine-DNA O
N
+ guanine DNA
HN N
Cross-linked DNA N +
H2N N
Aziridinium ion
DNA-5'-phosphate-deoxyribose
Step 5: Hydrolytic depurination
2 DNA (damaged)
Cl Cl
R
guanine CH2 CH2 N CH2 CH2 guanine
FIGURE 37.1 DNA destruction through nitrogen mustardmediated alkylation.

this is happening in a tumor cell, the therapeutic goal has H

O O
H
b Cl
been accomplished. If it is happening in a healthy cell, H b H Cl
particularly one with a short half-life, then the patient R
a N R
N
may experience side effects that can be use-limiting. Cl Cl
a + +
H
CHEMISTRY The structure of nitrogen mustards differs Active mustard O
only in the nature of the third group (R) attached to H
the amino nitrogen. This group, which can be either ali- b
phatic or aromatic, is the prime determinant of chemical 2HCl HCl
reactivity, oral bioavailability, and the nature and extent
of side effects. R R
An aliphatic nitrogen substituent (e.g., CH3) will release N N
HO OH Cl OH
electrons to the amine through bonds. This electronic HCl
enrichment enhances the nucleophilic character of the Inactive Cl
dehalogenated diol
lone pair of electrons and increases the speed at which OH
the + -carbon of the mustard will be attacked. Whether N R
in a tumor cell or a healthy cell, as soon as the aziridinium

+ +
ion forms, it will react with unpaired DNA and/or other H
cell nucleophiles, such as electron-rich SH (mercapto or O
H
sulfhydryl), OH (hydroxyl), and NH (amino) groups of
amino acids on enzymes or membrane-bound receptors. FIGURE 37.2 Aqueous decomposition of nitrogen mustards.
The bodys water can also react with (and inactivate) the
aziridinium ion. The intra- and intermolecular reactions
designated as steps 1 through 4 in Figure 37.1 happen an inactive, highly ionized, and water-soluble thiosulfate
so rapidly that almost no chance exists for tissue or cell ester that can be washed away (Fig. 37.4). The affected
specificity, which means a greatly increased risk of serious tissue should also be treated with an ice compress for 6
side effects and use-limiting toxicity. to 12 hours.
Conversely, an aromatic nitrogen substituent (e.g., Mechlorethamine is marketed in hydrochloride salt
phenyl) conjugated with the mustard nitrogen will sta- form to provide water solubility for intravenous or intra-
bilize the lone pair of electrons through resonance. cavitary administration. The strong electron-withdrawing
Resonance delocalization significantly slows the rate of effect of the two chlorine atoms reduces the pKa of
intramolecular nucleophilic attack, aziridinium ion for- mechlorethamine to 6.1, which gives a ratio of un-ionized
mation, and DNA alkylation. Aromatic mustards have a to ionized drug forms of approximately 20:1 at pH 7.4. This
reactivity sufficiently controlled to permit oral admin- agent is too reactive for oral administration and too toxic
istration and attenuate the severity of side effects. The to use alone. In addition to severe nausea and vomiting,
higher stability also provides the chance for enhanced tis- myelosuppression (lymphocytopenia and granulocytope-
sue selectivity by giving the intact mustard time to reach nia), and alopecia, it can cause myelogenous leukemia
malignant cells before generating the electrophilic aziri- with extended use due to its mutagenic/carcinogenic
dinium ion. effects on bone marrow stem cells. Mechlorethamine
Nitrogen mustards can decompose in aqueous media is still used in regimens for cancers of the blood (e.g.,
through formation of the inactive dehalogenated diol Hodgkins disease, chronic myelocytic leukemia, chronic
shown in Figure 37.2. Both the mustard nitrogen (path- lymphocytic leukemia); fortunately, safer and still highly
way a) and the oxygen of water (pathway b) can act as potent antineoplastic agents are now available.
nucleophiles to advance this degradative process. The
decomposition reactions can be inhibited if the nucleo- Melphalan This aromatic mustard, used primarily in the
philic character of these atoms is eliminated through treatment of multiple myeloma, is able to stabilize the
protonation, so buffering solutions to a slightly acidic pH lone pair of electrons on the mustard nitrogen through
helps to enhance stability in aqueous solution. resonance with the conjugated phenyl ring, slowing the
formation of the reactive aziridinium ion. The l-isomer
SPECIFIC DRUGS (FIG. 37.3) of the amino acid phenylalanine (l-Phe) was purpose-
Mechlorethamine Hydrochloride Mechlorethamine is fully incorporated into this antineoplastic agent because
the only aliphatic nitrogen mustard currently on the U.S. naturally occurring lamino acids are preferentially
market. Its use is limited by extremely high reactivity, transported into cells by the action of specific amino acid
which leads to rapid and nonspecific alkylation of cellu- carrier proteins. It was assumed that the l-Phe would
lar nucleophiles and excessive toxicity. It is a severe vesi- act as a homing device and actively transport the toxic
cant, and if accidental skin contact occurs, the drug must mustard inside the tumor cells, but some studies indicate
be inactivated with 2% sodium thiosulfate (Na2S2O3) that melphalan enters cells through facilitated diffusion
solution. This reagent reacts with the mustard to create rather than by active transport (17).

Nitrogen mustards and aziridine-mediated alkylators:
Cl
H Cl Cl Cl
NH2 N N
Cl Cl
N N CH2 C COOH N COOH HOOC(CH2)3
H N Cl
CH3
Cl Cl CH3
Mechlorethamine
hydrochloride Melphalan Chlorambucil Bendamustine
(Mustargen) (Alkeran) (Leukeran) (Treanda)
Nitrosoureas:
Cl Cl OH CH OH
2
O O O O S O O
P N P NH N P N Cl Cl O OH
N N O
NH N N Cl
H N N H3C N C NH
Cl Cl O N H OH
O N O N
Cyclophosphamide Ifosfamide Thiotepa
(Cytoxan) (Ifex) (Thioplex) Carmustine Lomustine Streptozocin
(BiCNU) (CeeNU) (Zanosar)
DNA methylators:
O O O Miscellaneous DNA alkylators:

C NH C NH2 C NH2
Cl N
H N (H3C)2N N N(CH3)2
H CH3
H3C N N CH2 N N N N N N N N CH3SO2 O (CH2)4 O SO2CH3
H H CH3
N
O N N(CH3)2
CH3
Procarbazine hydrochloride Dacarbazine Temozolomide Altretamine Busulfan
(Matulane) (DTIC-Dome) (Temodar) (Hexalen) (Myleran)
Organoplatinum complexes: O
C CH3
O H2N NH2 O
NH3
O H3N N H3N NH2
H3N Cl Pt Pt Pt CH3
O O Pt
Pt O NH3 Cl Cl Cl Cl
H3N Cl O O
O O C CH3
Cisplatin Carboplatin Picoplatin O
Oxaliplatin
(Platinol-AQ) (Paraplatin) (Eloxatin) Satraplatin
(investigational)
FIGURE 37.3 DNA cross-linking agents.
Because the lone pair of electrons of melphalan Chlorambucil Like melphalan, chlorambucil has good
(and other aromatic mustards) is less reactive than oral bioavailability (which is decreased in the presence
the lone electron pair on aliphatic mustards, there is a of food) and the potential to induce nonlymphocytic
greater opportunity for distribution to cancer cells and leukemia. This drug is active intact and also undergoes
a decreased incidence of severe side effects. There is a -oxidation to provide an active phenylacetic acid mus-
lower incidence of nausea and vomiting compared to tard metabolite, which is responsible for some of the
mechlorethamine, but patients still experience myelo- observed antineoplastic activity. It is used in the palliative
suppression, which can be severe. This drug is also muta- treatment of chronic lymphocytic leukemia, malignant
genic and can induce leukemia. lymphoma, and Hodgkin disease.
Melphalan is orally active, but absorption can be
erratic. Absorption is decreased with food, but dosing HOOCCH2 N(CH2CH2Cl)2
regimens do not demand an empty stomach. The hydro-
chloride salt is available for intravenous administration,
Phenylacetic acid mustard (an active chlorambucil metabolite)
but the risk of serious side effects is higher. Melphalan
distributes into body water, so toxicity can be pronounced
in dehydrated patients or in those with renal dysfunction. Bendamustine Hydrochloride Bendamustine is an excel-
Dehydration can be corrected, but dosage adjustments lent chemical example of the adage everything old is new
should be considered in patients with renal disease. again. First synthesized in 1963, serious interest in it as a

agents (e.g., the anticancer monoclonal antibody ritux-

4 Na imab and/or the topoisomerase poison mitoxantrone).
CH3 O
N
It undergoes minor CYP1A2-catalyzed N-demethylation
Cl Cl + 2 O S O
and -hydroxylation. While active, these metabolites are
S
2NaCl
clinically insignificant. There is currently no evidence of
serious metabolism-based interactions or toxicities asso-
ciated with bendamustine; however myelosuppression,
CH3
N
hypersensitivity/anaphylaxis, and skin reactions have
Na O2S2O OS2O2 Na been noted with its use. Pretreatment with antihistamines
and corticosteroids can help to minimize infusion reac-
Inactive thiosulfate ester
tions, a major cause of drug discontinuation.
FIGURE 37.4 Mechlorethamine inactivation by sodium thiosul-
N(CH2CH2Cl)2 N(CH2CH2Cl)2
fate. N H N
HOOC (CH2)3 HOOC (CH2)2 C
N N
OH
H CH3
viable therapeutic agent surfaced only recently after sev-
eral well-designed and appropriately executed clinical tri- N-Desmethylbendamustine Hydroxybendamustine
als documented its value in the treatment of hematologic (Bendamustine metabolites)
cancers, specifically chronic lymphocytic leukemia (CLL)
and non-Hodgkins lymphoma (NHL). Bendamustine Cyclophosphamide Cyclophosphamide is a chiral pro-
is the N-methylbenzimidazole analog of chlorambucil, drug antineoplastic agent requiring activation by meta-
and the substitution of this purine-like aromatic ring was bolic and nonmetabolic processes (20) (Fig. 37.5). The
purposefully done to promote an antimetabolite mecha- initial metabolic step is mediated primarily by CYP2B6
nism along with DNA alkylation. DNA damage is more (and, to a lesser extent, by CYP3A4 and CYP2C isoforms)
extensive and less repairable than that induced by other and involves regioselective hydroxylation at C4 of the
alkylating agents, and the drug is unique in its ability to oxazaphosphorine ring to generate a carbinolamine
stimulate p21 and p53-induced apoptosis, S-phase cell (20,21). This hydroxylation reaction must occur before
cycle arrest, and mitotic catastrophe (18). The risk of the molecule will be transported into cells, and approxi-
acquired resistance and cross-resistance appears lower mately 90% of an administered dose will be appropriately
than with other DNA alkylators (19). converted (20). CYP3A4 and CYP2B6 stereospecifi-
Unlike chlorambucil, bendamustine is given only cally catalyze an inactivating N-dechloroethylation reac-
intravenously on days 1 and 2 of a 21-day (NHL) or tion on the R and S isomers, respectively, which yields
28-day (CLL) cycle. It can be given alone or, in the case highly nephrotoxic and neurotoxic chloroacetaldehyde
of slow-growing, refractory, and/or relapsed (indolent) (20,21). Chloroacetaldehyde toxicity is accompanied by
lymphomas, in combination with other antineoplastic glutathione depletion, indicating that, as expected, this
Acrolein
O (uro- and nephrotoxic)
C H3PO4, NH3
N(CH2CH2Cl)2 H
O N(CH2CH2Cl)2 N(CH2CH2Cl)2 O
O Cl
P P P
Hydrolysis H2N O O H
HN O CYP2B6/3A4 HN O O N
P N
Decomposition Decomposition
HO H2N
Cl Cl Cl
H O
Cyclophosphamide Carbinolamine Aldophosphamide Phosphoramide mustard Bis(-chloroethyl)
(Prodrug) (transported into cells) (transported into cells) pKa = 4.75 (trapped in cells) amine
O
Cl CH2 CH Cyclization Cyclization
CYP3A4 Chloroacetaldehyde
(N-Dechloroethylation) (nephro- and neurotoxic)
Cl
Cl Cl O NH
O NH2 O NH 2
P H
P P Cl Cl -H Cl
HN O + HN O N O N N
+H
Inactive metabolites 40 Aziridinium ion Protonated aziridine 30 Aziridine free
(major product at pH 7.4) base
FIGURE 37.5 Cyclophosphamide metabolism.

electrophilic by-product alkylates cysteine (Cys) residues O

H C CH2 CH2 S CH2-CH2-SO3
of critical cell proteins (22). Alkylation of lysine, adenos-
ine, and cytidine residues is also possible. Mesna adduct
(water soluble, excretable)
The CYP-generated carbinolamine undergoes non-
enzymatic hydrolysis to provide the aldophosphamide
either in the bloodstream or inside cells. If this hydrolysis HS-CH2-CH2 SO3
occurs extracellularly, the aldophosphamide is still able Mesna

to penetrate cell membranes to reach the intracellular HS Cys O
O
space. Once inside the cell, acrolein (a highly reactive H C C CH2
H C CH2 CH2 S Cys
,-unsaturated aldehyde) is cleaved via spontaneous H Bladder cells
-elimination, generating phosphoramide mustard. With Acrolein Alkylated Cys in bladder
a pKa of 4.75, the mustard will be persistently anionic at (generated in liver) (toxicity)
intracellular pH and trapped inside the cell.
The fate of phosphoramide mustard is varied. Most of GSH
in liver Cys-SH
it cyclizes to form the quaternary aziridinium ion, which
alkylates DNA in the manner of all mustards. Some of GSH
it will decompose, losing phosphoric acid (H3PO4) and O O
ammonia (NH3) and leaving the naked bis(-chloroethyl) H C CH2 CH2 GS H C C CH2
In bladder H
amine mustard. This secondary amine cyclizes in a man-
ner similar to the tertiary phosphoramide mustard, Acrolein
(released in bladder)
forming a tertiary aziridine (rather than a quaternary
aziridinium) species. The free tertiary aziridine can pro- FIGURE 37.6 Sulfhydryl alkylation by acrolein.
tonate at intracellular pH to provide the cationic aziri-
dine species, which is in equilibrium with the free base
form. Some electrophilic character is lost, but the carbon the risk of bladder toxicity from acrolein, fluids should
atoms in both forms are still + enough to attract DNA be forced and the bladder irrigated. Mesna (Mesnex)
nucleophiles, albeit less vigorously. The net result is DNA is available as adjuvant therapy in case of overt toxicity
alkylation and cell death. Oxidation of oxazaphospho- or as a prophylactic protectant. A sulfhydryl reagent,
rine intermediates along the metabolic pathway by cyto- mesna is transported in the bloodstream as the inactive
solic alcohol or aldehyde dehydrogenase is inactivating oxidized disulfide (dimesna) and selectively reduced
(20). to the reactive sulfhydryl in the proximal tubules (20).
The need for metabolic activation in the liver means Once excreted into the bladder, the reactive SH group
lowered GI toxicity and less nonspecific toxicity for competes with Cys residues for the alkylating acrolein, as
cyclophosphamide compared with other DNA alkylat- shown in Figure 37.6. Mesna concentrates in the bladder
ing agents, but cyclophosphamide is not without its and will prevent damage to those cells. It does not con-
toxic effects. Acrolein, generated during the formation centrate to any appreciable extent in the nephron and,
of phosphoramide mustard, is a very electrophilic and therefore, is not good protection against cyclophospha-
highly reactive species, and it causes extensive damage mide-induced nephrotoxicity.
to cells of the kidney and bladder. While acrolein can be As effective as mesna is for preventing acrolein-
produced in kidney via CYP3A4-mediated metabolism, induced urotoxicity, it does little to spare the kidney
it is predominantly generated in liver, where it readily and nerve cells from chloroacetaldehyde, the other
conjugates with reduced glutathione (GSH) as expected toxic by-product of cyclophosphamide metabolism (25).
(23, 24). However, when the acrolein-GSH or mercaptu- Luckily, only approximately 10% of a standard dose of
ric acid conjugate is delivered to the bladder for excre- cyclophosphamide undergoes the dechloroethylation
tion, the conjugate can cause direct toxicity or cleave reaction, and most of the chloroacetaldehyde generated
to release electrophilic, reactive acrolein to the cells can be scavenged by GSH. However, since the competing
(23). Without additional GSH to re-scavenge liberated hydroxylation reaction is saturable, this percentage can
toxin, the acrolein will be attacked at its + terminal car- rise if higher doses are used (21).
bon by the nucleophilic SH of bladder cell Cys residues Cyclophosphamide is most commonly used in com-
(Fig. 37.6). More complex biochemical events involving bination with other antineoplastic agents to treat a wide
increased levels of preoxynitrite and subsequent lipid range of neoplasms, including leukemias and malignant
peroxidation also contribute to the observed urotoxicity lymphomas, multiple myeloma, ovarian adenocarcinoma,
(20). Physiologic results can include severe hemorrhage, and breast cancer. The drug is metabolized in the liver
sclerosis, and, on occasion (e.g., 5%), induction of blad- and eliminated via the kidney, with approximately 15%
der cancer. Acrolein also damages the nephron, particu- of a given dose being excreted unchanged. Doses should
larly when used in high doses, in children, in patients be reduced in patients with creatinine clearance levels less
with only one kidney, or when coadministered with than 30 mL/min. Interestingly, hepatic dysfunction does
other nephrotoxic agents (e.g., cisplatin). To minimize not seem to alter the metabolism of this drug, but caution

should be exercised in patients with inhibited CYP450 decoy (available in limited quantities) just cannot keep up.
enzymes or with a combination of factors that could The fact that this reaction can occur in the renal tubule,
negatively impact drug activation/inactivation pathways. generating chloroacetaldehyde right in the nephron,
Significant stereochemistry-based variation in the meta- contributes to a significantly higher nephrotoxicity that
bolic, enzyme inhibition, excretion, and toxicity profiles of can result in glomerular and renal tubular failure (27).
cyclophosphamide and related oxazaphosphorine antineo- Neurotoxicity is most commonly central in origin (e.g.,
plastic agents have been described in the literature (20). mental status dysfunction, seizures). Ultimately, both chlo-
roalkyl groups are lost before the compound is excreted.
Ifosfamide This cyclophosphamide analog has the It bears repeating that there is a significantly higher
two arms of the mustard on different nitrogen atoms. risk of bladder toxicity and nephrotoxicity with ifos-
Ifosfamide also requires metabolic activation (Fig. famide than with cyclophosphamide. The higher risks
37.7), but this time, it is the CYP3A4 isoform that con- of these toxicities result because significantly more
verts the majority of the dose to the carbinolamine, chloroacetaldehyde is generated through CYP3A4- and
with CYP2B6 taking on a minor supporting role (26). CYP2B6-mediated dechloroethylation. Although this
Because ifosfamide has a lower affinity for the hydrox- toxic by-product has been claimed to have some antitu-
ylating CYP3A4 and CYP2B6 enzymes, presumably as a mor activity (20), the biotransformation can take place in
result of steric hindrance, bioactivation proceeds at a the nephron, which generates chloroacetaldehyde right
slower rate (27). Doses three- to fourfold higher than where it will do the most unwanted cellular damage.
cyclophosphamide are required to achieve the same Ifosfamide is also more water soluble than cyclophospha-
antineoplastic result. mide and will concentrate in the renal system. In addi-
Unlike cyclophosphamide, dechloroethylation is a tion, higher doses must be administered to achieve the
significant metabolic pathway for ifosfamide, and up to same degree of antineoplastic action, so more molecules
60% of a standard dose will undergo this toxicity-inducing of acrolein and chloroacetaldehyde will be produced.
biotransformation (20,28). CYP3A4/3A5 catalyzes Because acrolein is generated during the bioactivation
approximately 70% of ifosfamide dechloroethylation, with of ifosfamide, the same precautions against hemorrhagic
CYP2B6 taking care of the remainder (21). So much chlo- cystitis that were previously outlined for cyclophospha-
roacetaldehyde is generated that the endogenous GSH mide must be taken: hydrate well, irrigate thoroughly,
and administer with mesna. As previously stated, mesna
will not prevent chloroacetaldehyde-induced toxicity.
Cl
GSH-based rescue agents such as N-acetylcysteine may
Cl Cl
have some benefit in attenuating ifosfamide-induced
Cl Cl Cl nephrotoxicity, but because they do not penetrate the
O NH O NH O NH
P P P bloodbrain barrier, they would be of little value in neu-
O N CYP3A4/2B6 O N Hydrolysis O N
H rotoxicity prophylaxis (20).
OH Ifosfamide is currently used as third-line therapy in
O
Ifosfamide Carbinolamine H testicular cancer, although it has also shown activity in a
(Prodrug) (transported into cells) number of other solid tumors and hematologic cancers.
Aldoifosfamide
(transported into cells) Patients on ifosfamide (but not cyclophosphamide) com-
CYP3A4/2B6 monly exhibit cerebral neuropathy attributed to the sig-
(N-Dechloro-
ethylation) nificantly higher levels of chloroacetaldehyde generated
O
C
Decomposition by this drug (20). In severe forms, CNS depression can
O H progress to coma and death.
Cl CH2 CH
Acrolein A new chiral oxazaphosphorine, trofosfamide, is cur-
Chloroacetaldehyde rently undergoing clinical trials for the palliative care of
(nephro- and neurotoxic) Cl
O
O solid tumor and NHL patients. Trofosfamide is rapidly
Cl P NH dechloroethylated at the mustard and oxazaphosphorine
Cl
NH nitrogen atoms to form ifosfamide (predominant) and
Cl
O NH O NH2 O NH2
Ifosfamide mustard cyclophosphamide, respectively (20).
P P P (trapped in cells)
O NH O N O NH
+ + O N(CH2CH2Cl)2
Cyclization
P
O N
Inactive metabolites Cl
O H
Cl N
P Cl Trofosfamide
HN O
Thiotepa Thiotepa, a tertiary aziridine, is less reac-

Protonated 30 aziridine
tive than quaternary aziridinium compounds and
FIGURE 37.7 Ifosfamide metabolism. is classified as a weak alkylator. It is possible for the

nitrogen atoms to protonate before reacting with DNA. and/or administration frequency should be increased
However, the electron-withdrawing effect of the sul- slowly, even if the initial response to the drug is sluggish,
fur atom decreases the pKa to approximately 6, which or unacceptable toxicity may result.
keeps the percentage ionized at pH 7.4 relatively low.
Thiotepa undergoes oxidative desulfuration, forming Nitrosoureas
an active cytotoxic metabolite known as TEPA (trieth- MECHANISM OF ACTION The nitrosoureas are unstable struc-
ylenephosphoramide). Both thiotepa and TEPA have tures that decompose readily in the aqueous environment
been proposed to alkylate DNA through the hydrolytic of the cell. Nonenzymatic fragmentation is stimulated by
release of aziridine, a more easily protonated structure, the loss of proton from the urea moiety. Cyclization of
which is, therefore, a more attractive target for DNA the resultant anion to an unstable oxazolidine (pathway
nucleophiles. In this mechanistic model, the parent A) is followed by decomposition to vinyl diazotic acid and
drug and the TEPA metabolite serve as carriers to trans- a substituted isocyanate, both of which release a gaseous
port aziridine-releasing drug across tumor cell mem- fragment (nitrogen and carbon dioxide, respectively) to
branes. (Fig. 37.8). Thiotepa, but not TEPA, is capable generate cytotoxic electrophiles (Fig. 37.9). Vinyl carbo-
of direct, regioselective DNA alkylation due to its slower cation, acetaldehyde, and 2-chloroethylamine generated
rate of intracellular hydrolysis (29). from the 2-chloroethylisocyanate moiety of carmustine
are all capable of alkylating DNA in the standard manner
O (30). A second decomposition mechanism (pathway B)
N P N
N
Triethylenephosphoramide O
(an active thiotepa metabolite) CH CH2 + H3C C H
Vinyl carbocation Acetaldehyde

Thiotepa is most commonly employed in the treat-
ment of ovarian and breast cancers, as well as papillary CO2 + H2N R
N2 + CO2
carcinoma of the bladder. Thiotepa and its TEPA metab-
olite readily enter the central nervous system (CNS) after H O
systemic administration, leading to dizziness, blurred HO N N CH CH2 + O C N R O N N
vision, and headaches. More critically, these agents are N R
also severe myelosuppressants and can induce leukope- Vinyl diazotic acid isocyanate Oxazolidine derivative
nia, thrombocytopenia, and anemia. Patients treated
Cl
with thiotepa are at high risk for infection and hemor-
rhage. Oral absorption is unreliable, so thiotepa is either A
given intravenously, or instilled intravesically in the treat-
A
ment of bladder cancer. Even when administered locally H
O
in bladder cancer, high levels of this lipophilic drug B O
Cl
N N R Cl
reach the systemic circulation, resulting in bone marrow H N N R
O N
depression. Patients have died from myelosuppression O N
after intravesically administered thiotepa. The drug also Nitrosourea
causes damage to the hepatic and renal systems. Dose B
Cl
S O N
+ O C N R
N P N N P N 2 DNA guanine N
N N O
N2 + CO2 H Isocyanate
H2O
DNA
Cl
nucleophile Thiotepa TEPA N
Lys NH2
Cl CH2 CH2 N
Direct DNA Hydrolytic aziridine release HO
alkylation DNA 2-Chloroethyl carbocation
O
nucleophile H
Lys N C NHR
S H
N DNA Carbamylated
N P N H2N Cl Cl
H H Lys
N
DNA Alkylated DNA DNA guanine CH2-CH2 guanine DNA
S (O)
Alkylated DNA N P OH Cross-linked DNA
N
FIGURE 37.9 Nitrosourea decomposition to cytotoxic electro-
FIGURE 37.8 Mechanism of thiotepa DNA alkylation. philes.

ultimately produces an electrophilic 2-chloroethylcarbo- these mispairs prompt point mutations during subse-
cation capable of DNA alkylation at guanine-N 7 and O 6, quent DNA replication cycles and trigger cell destruc-
as well as an isocyanate that can carbamylate amino acid tion through the activation of the normal postreplication
residues (e.g., lysine [Lys]). mismatch repair system. Patients who are able to repair
this damage through the action of O 6-alkylguanine-
SPECIFIC DRUGS (FIG. 37.3) DNA-alkyltransferase, which transfers the offending CH3
Carmustine and Lomustine Carmustine and lomustine group to a Cys residue on the alkyltransferase protein,
are both highly lipophilic chloroethylnitrosourea ana- will exhibit resistance to these agents, whereas those who
logs marketed for use in brain tumors and Hodgkins dis- underexpress this protein should respond well (32).
ease. Carmustine has also shown value in the treatment Since the alkyltransferase is irreversibly inactivated in the
of NHL and multiple myeloma, and it is given intrave- DNA rescue process, enzyme depletion with subsequent
nously or incorporated into biodegradable wafers that loss of DNA repair capability is a significant risk.
are implanted directly into the CNS after tumor resec- Procarbazine metabolism involves CYP1A and CYP2B
tion. The high lipophilicity of carmustine precludes a enzymes (33), and DNA alkylation operates through a free
totally aqueous intravenous formulation, and the drug radical mechanism (Fig. 37.10). The major degradation
is administered in 10% ethanol. Although carmustine pathway involves benzylic oxidation of azoprocarbazine,
degrades within 15 minutes of intravenous administra- producing methylhydrazine that generates a methyl radi-
tion, lomustine is stable enough for oral use and is mar- cal through an unstable diazene intermediate (34,35). In
keted in capsule form. Carmustine can also decompose addition to O 6, the reactive methyl radical formed can
in vitro if exposed to temperatures around 90F. Pure
carmustine is a low-melting solid, but the decomposed
product is an oil and, therefore, readily detected. Vials of O
H
carmustine that appear oily should be discarded. C N
Both carmustine and lomustine can induce throm-
bocytopenia and leukopenia, leading to hemorrhage
and massive infection. Acute (as well as potentially fatal H
H3C N N CH
delayed) pulmonary toxicity is also a risk. Pulmonary
toxicity is dose-related, and individuals who received the Minor pathway
drug in childhood or early adolescence are at higher risk
for the delayed reaction. The grand mal seizures that
O O
are possible from the wafer formulation of carmustine H H
C N C N
appear to result from the wafer rather than from the O2
nitrosourea. Resistance to carmustine involves upregula-
tion of O 6-methylguanine-DNA methyltransferase with H H
H3C N N CH2 H2O2 H3C N N CH2
the subsequent repair of drug-induced DNA damage,
and possibly sequestration by neuroprotective metallo- Procarbazine Azoprocarbazine
thionein proteins (31).
Streptozocin The glucopyranose moiety of streptozocin

confers both islet cell specificity and high water solubility CYP1A/2B Major pathway
to this nitrosourea-based antineoplastic. As a result, it is
used exclusively in metastatic islet cell carcinoma of the
O
pancreas and is administered intravenously in D5W or H H
H3C N NH2 C N
normal saline. Lacking the 2-chloroethyl substituent of +
carmustine and lomustine, it is much less reactive as a Methylhydrazine O CH
DNA alkylating agent. Myelotoxicity, while not unknown,
is relatively rare. However, cumulative, dose-related renal
Xanthine
toxicity may be severe or fatal, and 67% of patients receiv- oxidase
ing this drug will exhibit some kidney-related pathology. H3C N NH CH3 + H + N2
O
Good hydration is essential to successful therapy, and kid- Methyldiazene
H
C N
ney function should be monitored weekly.
Guanine methylation O C
Procarbazine and Triazines
at O6, C8, N7 OH
MECHANISM OF ACTION Procarbazine and the triazenes N-Isopropylterephthalamic
dacarbazine and temozolomide act by different mech- acid (major urinary
metabolite)
anisms, but they all exert an antineoplastic effect
through the O 6-methylation of guanine nucleotides. FIGURE 37.10 Procarbazine metabolism and mechanism of
O 6-Methylguanine pairs preferentially with thymine, and action.

alkylate the C 8 and N 7 positions of guanine. In contrast, noted when alcohol is concomitantly consumed because
the triazenes methylate DNA guanine via diazomethane the drug also inhibits enzymes involved in ethanol
and/or methyl carbocation generated in situ. Although metabolism.
temozolomide is converted to the diazomethane pre-
cursor 3-methyl-(triazen-l-yl)imidazole-4-carboxamide Dacarbazine This DNA methylating agent is admin-
(MTIC) through nonenzymatic mechanisms, the con- istered intravenously as a single agent in the treat-
version of dacarbazine to MTIC depends on the action ment of malignant melanoma and in combination with
of CYP1A1 and CYP1A2 enzymes, with a smaller contri- other agents in the treatment of metastatic melanoma.
bution by CYP2E1 (Fig. 37.11) (33, 36). The O 6 and N 7 Approximately 40% of the drug is excreted unchanged,
positions of guanine are the most vulnerable to triazene but both the 5-aminoimidazole-4-carboxamide (AIC,
methylation. formed through the action of CYP1A enzymes) and the
carboxylic acid (AIC hydrolysis product) are major uri-
SPECIFIC DRUGS (FIG. 37.3) nary metabolites (Fig. 37.11). Leukopenia and thrombo-
Procarbazine Hydrochloride This methyl radical genera- cytopenia are the most common side effects and can be
tor is used predominantly in the treatment of Hodgkins fatal. Patients are also at risk for hepatotoxicity, including
disease. It is administered as part of a multidrug regimen hepatocellular necrosis.
that also includes a nitrogen mustard (mechloretha-
mine), a mitosis inhibitor (vincristine), and prednisone. Temozolomide This imidazolotetrazine derivative is
It is administered as capsules and is well absorbed after administered orally in capsule form for the treatment of
oral administration. Procarbazine is extensively metabo- glioblastoma multiforme or in patients with anaplastic
lized in the liver, and 70% of an administered dose is astrocytoma who have not responded to procarbazine or
excreted in the urine as N-isopropylterephthalamic acid the nitrosoureas. Oral absorption is rapid and complete.
(Fig. 37.10). In addition to methylating DNA guanine While CYP450 enzymes are not extensively involved in
residues, it is proposed to inhibit the de novo synthe- temozolomide metabolism, less than 6% of the drug is
sis of proteins and nucleic acids. Procarbazine inhibits excreted unchanged in the urine. Women clear the drug
monoamine oxidase, leading to several significant and less effectively than men and have a higher incidence of
potentially fatal drugdrug and drugfood interactions. severe neutropenia and thrombocytopenia in the initial
Facial flushing and other disulfiram-like symptoms are therapy cycle. Food decreases temozolomide absorption,
and myelosuppression is the most significant adverse
effect. Resistance involves drug-induced damage reversal
O by O 6-methylguanine-DNA methyltransferase, and some
O CH2 O O authors are advocating the design of inhibitors of this
C NH2 C NH2 C NH2 potential target for use in combination with temozolomide
N N N
CH3 CYP1A CH3 and other guanine O 6-methylating antineoplastics (37).
N N N N N N N N N NH2
H CH3 H H H
Miscellaneous DNA Alkylating Agents (Fig. 37.3)
Dacarbazine MTIC 5-Aminoimidazole- ALTRETAMINE This unique hexamethylmelamine structure
4-carboxamide
(AIC, major urinary is believed to damage tumor cells through the production
O metabolite) of the weakly alkylating species formaldehyde, a product
Non -enzymatic
C NH2
N + of CYP450-mediated N-demethylation. Administered
orally, altretamine is extensively metabolized on first pass,
N N
N CH3 N N producing primarily mono- and didemethylated metabo-
O N or lites. Additional demethylation reactions occur in tumor
CH3 O Diazomethane
cells, releasing formaldehyde in situ before the drug is
Temozolomide HN N excreted in the urine. The carbinolamine (methylol)
N2
H2N N N intermediates of CYP450-mediated metabolism can also

generate electrophilic iminium species that are capable
DNA 5'-phosphate-deoxyribose CH3 of reacting covalently with DNA guanine and cytosine res-
Methyl carbocation idues, as well as protein (Fig. 37.12). Iminium-mediated
DNA cross-linking and DNA-protein interstrand cross-
CH3 linking, mediated through both the iminium inter-
O
mediate and formaldehyde, have been demonstrated
N N
(38,39), although the significance of DNA cross-linking
H2N N N on altretamine antitumor activity is uncertain. Resistance
DNA 5'-phosphate-deoxyribose to altretamine has been shown to parallel resistance to
formaldehyde-induced cytotoxicity (38). Its use currently
O6-Methyguanine-DNA
is restricted to patients with ovarian cancer who have not
FIGURE 37.11 Metabolic activation of triazenes. responded to organoplatinum therapy. The toxicities

N
CH2OH DNA interstrand cross-linking has been shown to vary
(H3C)2N N N(CH3)2 (H3C)2N N
CH3 with the length of the alkyl chain between sulfonate esters,
N N
CYP450
N N with the tetramethylene-containing busulfan showing less
N(CH3)2 N(CH3)2 interstrand cross-linking capability than hexamethylene,
methylene, or octamethylene analogs (41). Intrastrand
Altretamine Carbinolamine
(Hexamethylmelamine, metabolite cross-linking also occurs, preferentially at 5-GA-3 but also
HMM) at 5-GG-3 sequences (42). Alkylation of Cys sulfhydryl
groups is yet another mechanism of cytotoxicity. Busulfan
O
CH2
HCH is used in the treatment of CML and can be administered
(H3C)2N N N
CH3 either orally or by intravenous infusion. Serious bone mar-
N N row hypoplasia and myelosuppression are possible with
N(CH3)2 H this agent, and recovery from busulfan-induced pancyto-
DNA-protein (H3C)2N N N
cross-linking CH3 penia can take up to 2 years.
Reactive N N
iminium ion
N(CH3)2 Organoplatinum Complexes
Guanine, protein, MECHANISM OF ACTION Organoplatinum antineoplastic
cytosine nucleophiles Pentamethylmelamine
(PMM)
agents contain an electron-deficient metal atom that
acts as a magnet for electron-rich DNA nucleophiles.
CH2 DNA or protein Like nitrogen mustards, organoplatinum complexes are
(H3C)2N N N bifunctional and can accept electrons from two DNA
CH3
N N
nucleophiles. Intrastrand cross-links most frequently
occur between adjacent guanine residues referred to
N(CH3)2
as diguanosine dinucleotides (60% to 65%) or adja-
Alkylated DNA or protein cent guanine and adenine residues (25% to 30%) (43).
Interstrand cross-linking, which occurs much less fre-
FIGURE 37.12 Altretamine metabolism and mechanism of action. quently (1% to 3%), usually involves guanine and ade-
nine bases (44).
induced by altretamine are GI, neurologic, and hema- CHEMISTRY All the currently marketed organoplatinum
tologic in nature. An orally active liposomal formulation anticancer agents are Pt(II) complexes with square planar
containing sodium deoxycholate has been investigated geometry, although an octahedral Pt(IV) complex cur-
but is not currently commercially available (40). rently is undergoing clinical trials. Platinum is inherently
electron deficient, but the net charge on the organome-
BUSULFAN Chemically, busulfan is classified as an alkyl tallic complex is zero due to the contribution of electrons
sulfonate. One or both of the methylsulfonate ester moi- by two of the four ligands bound to the parent structure.
eties can be displaced by the nucleophilic N 7 of guanine, Most commonly, the electron-donating ligand is chloride.
leading to monoalkylated and cross-linked DNA as shown Before reacting with DNA, the electron-donating ligands
in Figure 37.13. The extent of alkyl sulfonatemediated are displaced through nucleophilic attack by cellular
CH3SO3
CH3SO2 O (CH2)4 O SO2CH3 CH3SO2 O (CH2)4 guanine-DNA

CH3SO3
Busulfan Monoalkylated DNA
O O
HN N N
HN
H2N N N N
H2N N
DNA-5'-phosphate-deoxyribose DNA-5'-phosphate-deoxyribose
O O
HN N N NH
H2N N N N N NH2
DNA-5'-phosphate-deoxyribose deoxyribose-5'-phosphate-DNA
Cross-linked DNA
FIGURE 37.13 Busulfan-mediated DNA alkylation.

water. When the displaced ligands are chloride anions in a short plasma half-life of less than 30 minutes. It is
(e.g., cisplatin), the chloride-poor environment of the eliminated predominantly via the kidney, but approxi-
tumor cell facilitates the process, driving the generation mately 10% of a given dose undergoes biliary excretion.
of the active, cytotoxic hydrated forms (Fig. 37.14). Since It is highly nephrotoxic and can cause significant damage
the original ligands leave the metal with their electrons, to the renal tubules, especially in patients with preexisting
the hydrated organoplatinum molecule has a net positive kidney disease, with one kidney, or who are concurrently
charge (45). receiving other nephrotoxic drugs (e.g., cyclophospha-
mide or ifosfamide). Dosages should be reduced in any
Cl Cl of these situations. Clearance decreases with chronic
Pt therapy, and toxicities can manifest at a later date.
H 3N NH3 To proactively protect against kidney damage, patients
should be aggressively hydrated with chloride-containing
Cisplatin (square planar geometry)
solutions. Saline or mannitol diuretics can be adminis-
tered to promote continuous excretion of the drug and
The hydrated platinum analogs are readily attacked its hydrated analogs. Sodium thiosulfate, which accumu-
by DNA nucleophiles (e.g., the N 7 of adjacent guanine lates in the renal tubules, has also been used to neutralize
residues) due to the net positive charge that has been active drug in the kidneys in an effort to avoid nephro-
regained on the Pt atom (Fig. 37.14). The DNA bases toxicity (Fig. 37.15). The reaction of sodium thiosul-
become coordinated with the platinum, and in the cis fate with cisplatin in the serum is much less significant
configuration, DNA repair mechanisms are unable to because the drug does not concentrate there, and what is
permanently correct the damage. The net result is a there is very strongly bound to serum proteins. The very
major change in DNA conformation such that base pairs strong protein binding explains why dialysis, even when
that normally engage in hydrogen bond formation are prolonged, cannot rescue patients from cisplatin toxicity.
not permitted to interact. The two ammine ligands of the Cisplatin is a very severe emetogen, and vomiting
complex are bound irreversibly to the Pt atom through almost always occurs unless antiemetic therapy is coad-
very strong coordinate covalent bonds. They cannot be ministered. Myelosuppression and ototoxicity that can
displaced by DNA nucleophiles, but they do stabilize the lead to irreversible hearing loss can also occur with cis-
cross-linked DNAplatinum complex by forming strong platin use. A recent study has shown that, in medulloblas-
ion-dipole bonds with the anionic phosphate residues on toma patients 3 to 21 years of age, bolus administration
DNA. The DNA distortion prompts a futile cycle of dam- of the thiol-generating prodrug amifostine, both imme-
age recognition and repair before giving up the ghost diately before and again during cisplatin infusion, signifi-
and succumbing to cell cycle arrest and apoptosis. cantly decreased ototoxicity and the need for a hearing
aid after therapy (46). Alkaline phosphatase, amifostines
SPECIFIC DRUGS (FIG. 37.3) activating enzyme, shows a higher activity in normal tis-
Cisplatin The simplest of the organometallic antineo- sue compared to tumor tissue. This allows for higher
plastic agents, cisplatin is used intravenously in the treat- levels of drug destruction in nontarget healthy cells and
ment of metastatic testicular and ovarian cancer and provides protection against unwanted toxicity without
advanced bladder cancer. It is rapidly hydrated, resulting compromising cisplatins antineoplastic action.
O Alkaline
Cl OH SH
S P H2N N
H3N NH3 H3N NH3 H2N N OH phosphatase H
H
Pt Pt
H2O Cl OH2
Cl Cl Amifostine (a thiophosphate Active thiol metabolite
Cisplatin monoaquo form prodrug)
Cisplatin (active)
H2O Resistance to cisplatin therapy can be intrinsic in

Cl
colorectal, lung, and breast cancer, or acquired after
multiple courses of therapy (e.g., in ovarian cancer).
2 H2O
H3N NH3 H3N 2 NH3
Pt
Cisplatin diaquo
Pt
form (active) Na Na
H2O OH2 H3N NH3
N7 N7 H3N NH3 O
+ 2 O S O Pt
Pt
DNA Guanine Guanine DNA N7 N7 S O3 S 2 S2O3
Cl Cl
DNA Guanine Guanine DNA 2 NaCl Na
Na
Cross-linked DNA Diguanosine dinucleotide Cisplatin Sodium thiosulfate Water soluble adduct
FIGURE 37.14 Cisplatin activation and DNA cross-linking. FIGURE 37.15 Cisplatin inactivation by sodium thiosulfate.

Resistance is mediated through several distinct mecha- Oxaliplatin This Pt(II) complex loses oxalate dianion
nisms, including: 1) compromised carrier-mediated ( OOC-COO) in vivo to form the mono- and dihydrated
cellular transport via the copper transporting pro- diaminocyclohexane (DACH) platinum analogs shown
tein CTR1; 2) enhanced intracellular inactivation in Figure 37.16. The trans-(R,R)-DACH structure serves
through drug trapping in vesicles; 3) drug inactivation as the carrier for the cytotoxic hydrated platinum and
through conjugation to Cys and/or methionine (Met)- extends into the major groove of DNA when the DNA
containing GSH and metallothionein proteins; and 4) Pt complex forms (48). Hydrophobic DNA intrusion is
increased DNA repair and/or tolerance to cisplatin- believed to contribute to the cytotoxicity of this organo-
induced DNA damage (47). Regarding the latter mech- metallic. Oxaliplatin engages primarily in intrastrand
anism, cisplatin damage can be successfully repaired cross-linking with diguanosine dinucleotides, adjacent
by nucleotide-excision repair proteins (NERs), which A-G nucleotides, and guanines that are separated by one
remove platinum-damaged segments from the DNA, nucleotide (G-X-G). Interstrand cross-linking, although
and these proteins are often upregulated in cisplatin- less common, also occurs.
resistant tumors. Cisplatin (and carboplatin)DNA The adduct formed between oxaliplatin and DNA
adducts are also recognized by mismatch repair pro- diguanosine dinucleotides is conformationally distinct
teins (MMRs). The downregulation of MMRs in cis- from the adduct formed with cisplatin or carboplatin.
platin (and carboplatin)treated cancer cells induces Specifically, whereas the cisplatin diguanosine dinucle-
resistance through the loss of an apoptotic response otide adduct bends the DNA by 60 to 80 degrees and
that normally follows several ill-fated attempts to repair presents a relatively wide minor groove, the oxaliplatin
organoplatinum-induced damage. Testicular tumors adduct produces a 31-degree bend with a comparatively
are particularly responsive to cisplatin due to their narrow minor groove (49). This distinct oxaliplatin con-
inherent deficiency in DNA repair processes. Cellular formation is believed to result from the steric impact of
efflux mediated by P-gp (a product of the ABCB1 gene), the (R,R)-DACH carrier, which permits the cis-NH3 moi-
a resistance mechanism common to natural product eties to hydrogen bond with a guanine-O 6, a bond that
anticancer agents, is not believed to be a component of the inactive (S,S)-isomer cannot make (50). The confor-
resistance to organometallics (47). mation of the oxaliplatin-DNA adduct is much less likely
Cisplatin and the other organoplatinum anticancer to be recognized by MMR proteins, and the effectiveness
agents react with aluminum and cannot be administered of oxaliplatin in MMR-deficient cells is, at least in part,
through aluminum-containing needles. The drug is pho- responsible for the lack of resistance that has plagued
tosensitive, is packaged in amber bottles, and must be cisplatin and carboplatin (51,52). Oxaliplatin is also less
protected from light. dependent on CRT1 active transporting proteins for intra-
cellular access and often retains activity in patients who
Carboplatin Carboplatin, another square planar are no longer responding to the first-generation organo-
Pt(II) complex, forms the same cytotoxic hydrated metallics. It is significantly less mutagenic, nephrotoxic,
intermediate as cisplatin but does so at a 10-fold slower hematotoxic, and ototoxic than cisplatin. Excretion is via
rate, making it a 20- to 40-fold less potent chemothera- the kidney. Oxaliplatin decomposes in alkaline media
peutic agent (47). The ultimate damage done to cells and should not be coadministered with drugs that will
as a result of carboplatin use approaches that of cis- increase the pH of the intravenous solution.
platin, but the side effect profile is significantly milder. Oxaliplatin is used in the treatment of metastatic colon
Suppression of platelets and white blood cells is the or rectal cancer, either alone or in combination with
most significant toxic reaction, and nonhematologic fluorouracil. Pulmonary fibrosis and peripheral sensory
toxicities (e.g., emesis, nephrotoxicity, and ototoxicity)
are rare. The plasma half-life of carboplatin is 3 hours,
and the drug is less extensively bound to serum pro-
teins than cisplatin. Excretion is still predominantly H2N NH2 H2O H 2N NH2
renal, however, and doses must be reduced in patients Pt Pt
with kidney disease. O OH2
O O
OH
Carboplatin is only approved for use in the treat- O
O O O
ment of advanced ovarian cancer, although clinical trials OOC COO
have shown that it may have a future in the treatment Oxaliplatin Oxaliplatin
of hormone-refractory prostate cancer. Carboplatin can H2O
be used in combination with docetaxel (often consid-
ered the standard of care for prostate cancer) and estra- DACH
mustine (a less commonly used mitosis inhibitor). This Oxaliplatin diaquo form
(active) H2N NH
drug has provided therapeutic benefit as a single agent 2
in patients whose cancer has progressed after docetaxel H2O
Pt
OH2
therapy. Unlabeled uses for carboplatin include combi-
nation therapy in lung and head and neck cancers. FIGURE 37.16 Activation of oxaliplatin.

neuropathies that can be life-threatening are known to trials in patients with small cell or non-small cell lung can-
occur. It has been proposed that the latter adverse effect cer are investigating the benefits of satraplatin as a single
is caused by oxalate-based chelation of intracellular Ca2+, agent and satraplatinpaclitaxel combination therapy,
which inhibits voltage-gated sodium channels in sensory respectively. Data analyzed to date suggest that satraplatin
nerve cells (53). This hypothesis is supported by the obser- (administered as a single agent) is as effective as cisplatin
vation that infusions of calcium or magnesium salts can or carboplatin in the treatment of small cell lung cancer
significantly attenuate oxaliplatin-induced neuropathy and ovarian cancer. Satraplatin is also being paired with the
without compromising therapeutic efficacy (54). In the pyrimidine antagonist capecitabine, the DNA polymerase
future, exploitation of genetic differences in the expression inhibitor gemcitabine, or the mitosis inhibitor docetaxel
of various repair proteins, growth factors, and metaboliz- in clinical trials in patients with advanced solid tumors.
ing enzymes may allow the tailoring of oxaliplatin therapy Satraplatin retains activity in cisplatin-resistant can-
based on an individuals pharmacogenetic profile (52). cers. Satraplatin-induced DNA damage is not recognized
by MMR proteins, and its higher lipophilicity liber-
Picoplatin Picoplatin is a Pt(II) organometallic cur- ates it from dependence on CTR1 for cellular uptake.
rently designated as an orphan drug for the treatment Resistance to satraplatin therapy can occur, but it is medi-
of small cell lung cancer. It is also being investigated for ated through the intracellular sequestering of the drug
use in platinum-sensitive ovarian cancer (in combina- in cytoprotective vesicles, a resistance pathway it shares
tion with paclitaxel), prostate cancer (in combination with other organometallics. Its toxicity profile is mild,
with docetaxel), and colorectal cancer (in combination with dose-related, but noncumulative, myelosuppres-
with fluorouracil/leucovorin). The name of this antineo- sion (particularly neutropenia and thrombocytopenia),
plastic is derived from the 2-methylpyridine (picoline) anemia, and diarrhea being the major use-limiting side
ring associated with the platinum atom. The intentional effects (47,51,55,56).
incorporation of bulk around the platinum decreases
intracellular inactivation through attack by the sulfhydryl- Topoisomerase Poisons
containing glutathione peptide and metallothionein pro- Topoisomerases are enzymes that control the degree of
teins, allowing continued efficacy in cisplatin-resistant DNA supercoiling and, in so doing, maintain proper
tumors. This platin is active by the intravenous and oral DNA structure during replication and transcription to
routes. Like carboplatin, the drug is not nephro- or neu- RNA (57). Topoisomerase II (TopII) cleaves double-
rotoxic, but does induce myelosuppression that reverses stranded DNA during the replication phase via a trans-
upon drug discontinuation (47,55). esterification reaction involving a topoisomerase tyrosine
residue and a terminal 5 phosphate but, through a
Satraplatin This asymmetrical organometallic agent reverse transesterification, repairs its own damage after
is a Pt(IV) complex. As with the Pt(II) complexes, the replication is complete (58). Topoisomerase I (TopI)
platinum has no net charge in the parent drug since its functions in essentially the same way, but cuts and reli-
original +4 charge has been neutralized by the dona- gates a single DNA strand. Antineoplastic agents that
tion of electrons from the chloride and acetate ligands. function as topoisomerase poisons stimulate the DNA
Unlike most marketed square-planar Pt(II) complexes, cleavage reaction but inhibit the DNA resealing activity
it is active by the oral route. Oral efficacy is enhanced by of the enzymes, leaving the DNA irreversibly damaged
administering the drug on an empty stomach, using a 5 and unable to replicate.
consecutive day regimen within a 28- to 35-day cycle. It Three chemically distinct classes of anticancer agents
is metabolized quickly in whole blood, producing up to can be classified as topoisomerase poisons: camptothe-
six metabolites. The major metabolite is the desacetoxy cins, epipodophyllotoxins, and anthracyclines (discussed
analog. As with other organoplatinum complexes, the under antineoplastic antibiotics).
diaquo form is active.
Camptothecins
MECHANISM OF ACTION Camptothecins are chiral, exten-
H3N H2N H 3N H 2N
sively conjugated, amine-containing pentacyclic lactones
Pt Pt
(Fig. 37.17). The biologic target of camptothecins is
Cl Cl H2O OH2
TopI, rather than the TopII enzyme that serves as the
Desacetoxysatraplatin Diaquo satraplatin receptor for the epipodophyllotoxins and anthracyclines.
(active) However, as noted earlier, the mechanism of antineo-
plastic action of both enzyme inhibitors is stabilization
Satraplatin is currently in clinical trials as a second-line of a cleavable ternary DNAenzyme complex that does
agent for the treatment of hormone-refractory prostate not permit the resealing of nicked DNA. Although the
cancer. Trials pairing satraplatin with prednisolone have fragmented DNA is capable of resealing in the absence
been particularly promising, with patients on the combi- of drug, when DNA replication forks encounter the frag-
nation therapy showing a 40% reduction in progression mented DNA, a double-stranded DNA break occurs, kill-
compared to patients on the corticosteroid alone. Other ing the cell.

Camptothecins
H3C CH3 Cl
C2H5 N
H H
9 7
N N C O O HO O
H O 10 A B CN 17 N
Cl N1 D N1
E O O
20 C2H5
C2H5 21
OH O OH O
Irinotecan hydrochloride (Camptosar) Topotecan hydrochloride (Hycamtin)
Epipodophyllotoxins
H H H
H3C O H3C O O
O O S O
HO O HO O HO O
O O O
HO H HO H HO H
O O O
O O O
O O O
O O O
H3CO OCH3 H3CO OCH3 H3CO OCH3

OH OPO3H2 OH
Etoposide (VePesid) Etoposide phosphate Teniposide hydrochloride

(Etopophos) (Vumon)
FIGURE 37.17 Camptothecins and epipodophyllotoxins: topoisomerase poisons.
The binding of camptothecins occurs in such a way as CHEMISTRY The parent camptothecin alkaloid, isolated
to stabilize a covalent DNAtopoisomerase bond at the from the bark of Camptotheca acuminata (the Chinese
point of single-strand breakage (tyrosine [Tyr] at 723 on xi shu or happy tree) (64), has antitumor activity, but
the human enzyme) but sterically keep a TopI Lys532 its limited water solubility necessitates delivery as the
residue from catalyzing the DNA religation reaction sodium salt of the significantly less active hydrolyzed lac-
(59,60). The binding pocket, located within the DNA tone. Lactonization of the hydroxy acid in acidic urine is
strand, is revealed only after the normal DNA nicking has significant, and elevated levels of active intact alkaloid in
occurred, explaining why these poisons preferentially the kidney account for the hemorrhagic cystitis induced
bind to the enzymeDNA complex rather than to unoc- by this compound.
cupied DNA or enzyme. The flat camptothecin ring sys- Camptothecins quinoline ring system is unsubsti-
tem intercalates DNA at the site of cleavage, mimicking tuted, but currently marketed analogs have a basic side
a DNA base pair (59). The crystal structures of human chain incorporated at either C9 (topotecan) or C10 (iri-
ternary complexes involving the parent alkaloid, camp- notecan), allowing the formation of water-soluble salts of
tothecin, and the semisynthetic analog, topotecan (Fig. the intact semisynthetic alkaloid. At pH 7.4, the active
37.17), have been solved, and important drugprotein lactone exists in equilibrium with the hydroxy acid hydro-
interacting entities are noted in Table 37.7 (5961). The lysis product, with the direction dictated by the extent
bulky substituents at C7, C9, and C10 of the marketed com- of binding to serum albumin. The preferential protein
pounds, which project into the major groove of DNA, do
not hinder binding.
Camptothecins are most toxic to cells undergoing TABLE 37.7 TopotecanTopoisomerase I Interactions
active DNA replication and cell division (e.g., they are
S-phase specific). Mechanisms of resistance are similar Topotecan Functional Group Topoisomerase I Residue
to those operational in many other classes of antineo-
Pyridine N1 Arg364
plastic drugs and include downregulation or mutation of
the target enzyme, downregulation of enzymes needed C10-OH Enzyme-associated water (H-bond)
for drug activation, and cellular efflux. Breast cancer
C17-pyridone carbonyl Asn722
resistance protein and multidrug resistance (MDR)
associated proteins, such as MAP-2 and MAP-3, rather C20-OH Asp533 (H-bond)
than P-gp, appear to mediate resistance to these agents
C21-lactone carbonyl Tyr723-phosphate, Lys532
(62,63).

binding of the lactone, which occurs with irinotecan, half-life of 11.5 hours (compared with 5.0 to 9.6 hours for
shifts the equilibrium to favor the production of the the prodrug parent) and is glucuronidated or sulfated
more active lactone, thus enhancing potency. at the C10 phenol before elimination. CYP3A4 also cleaves
Some authors have recently pondered whether the terminal piperidine ring through oxidation at the
camptothecins are making a clinical comeback (64). A -carbons. This is followed by hydrolysis of the resultant
quantitative study on camptothecin structureproperty amides, which produces inactive metabolites. Excretion
relationships has recently been published (65), as has of the parent drug and metabolites is renal (14% to 37%)
a review summarizing the current literature describing and, to a lesser extent, biliary.
outcomes in preliminary, preclinical, and clinical in vivo Delayed diarrhea induced by irinotecan is dose-
studies for camptothecins and various small and macro- limiting and potentially fatal, and vigorous loperamide
molecular analogs of the natural products (66). therapy should be instituted at the first sign of symp-
toms. Acute diarrhea is attributed to the drugs ability
SPECIFIC DRUGS (FIG. 37.17) to inhibit acetylcholinesterase and can be addressed
Irinotecan Hydrochloride In combination with fluoro- through anticholinergic pretreatment. Pretreatment
uracil, this prodrug camptothecin analog is considered also helps patients to avoid cholinergic syndrome, a
first-line therapy in the treatment of metastatic colorectal collection of annoying side effects that include flush-
cancer. It has also shown efficacy in small cell and non ing, sweating, blurred vision, lacrimation, and less
small cell lung cancers when used in combination with commonly, bradycardia. Camptothecins are also myelo-
cisplatin. Given intravenously, the drug is slowly bioacti- suppressive, and leukoneutropenia can be severe,
vated in the liver through hydrolysis of the C10-carbamate particularly in patients with elevated bilirubin levels.
ester. The catalyzing enzyme is a saturable carboxylester- Extensive biotransformation also demands cautious
ase known as irinotecan-converting enzyme. Levels of use of irinotecan in patients with hepatic dysfunction.
active metabolite, known as SN-38 (Fig. 37.18), are 50- Prophylactic antiemetic therapy should be given at least
to 100-fold lower than the parent drug, but preferential 30 minutes before the administration of irinotecan to
protein binding of the lactone (95%) permits significant minimize the nausea and vomiting associated with this
plasma levels of the optimally active SN-38 compared anticancer agent.
to the hydroxy acid metabolite. SN-38 has a terminal It is now recognized that patients, particularly those of
Asian heritage, may be pharmacogenetically predisposed
C2H5 C2H5 to life-threatening toxicity from camptothecin therapy.
HO HO
O Hydrolysis O Variations in expression of gene(s) involved in the inacti-
N N
N Lactonization N
OH vating glucuronidation of irinotecan (specifically overex-
O OH pression of the low activity UGT1A1*6 allele) are deemed
C2H5 C2H5 responsible, and genotyping efforts are being made to
OH O OH O
Phenolic Hydroxy acid more safely and effectively individualize therapy in at-
metabolite (SN-38, active) metabolite (less active) risk individuals (67,68).
Hepatic irinotecan-
UDPGA Topotecan Hydrochloride This active camptothecin ana-
glucuronyl transferase
converting enzyme log is used by the intravenous route in the treatment of
ovarian and small cell lung cancer that has not responded
Irinotecan (inactive) C2H5 to first-line therapy. Myelosuppression, particularly neu-
Glucuronide O O tropenia, is use-limiting and has precluded combina-
N
CYP3A4 tion therapy with other bone marrow-suppressing drugs.
N
O
Thrombocytopenia and anemia occur in approximately
C2H5 one-third of treated patients. Schedules that call for daily
OH O (for 5 days) administration can also result in serious
COOH O C2H5
H mucositis and diarrhea.
N N C O O SN-38-O10-
N glucuronide Topotecan elimination is biphasic with a terminal
N (inactive) half-life of 2.0 to 3.5 hours. Lactone hydrolysis is rapid,
O and binding to serum proteins is limited to between 25%
+ C2H5
OH O and 40%. CYP3A4-mediated N-dealkylation to mono- and
di-dealkylated metabolites occurs to a limited extent,
O C2H5
and the O-glucuronides that form at multiple points
H2N N C O O
N
along the metabolic path are excreted via the kidney
N (Fig. 37.19). Extensive renal clearance demands dosage
O adjustment in patients with kidney disease. A nanoli-
Inactive metabolites C2H5
posomal formulation of topotecan with an enhanced
OH O
cytotoxic and pharmacokinetic profile is currently in
FIGURE 37.18 Irinotecan metabolism. development (69).

CH3 a carbene-generating diazirine photoaffinity label (71),

N CH3
and a virtual library of 143 epipodophyllotoxin deriva-
CH2
HO
tives has been docked to a three-dimensional human
Hydrolysis O
Topotecan N TopII receptor model in order to identify key drug
OH
(active) Lactonization N enzyme interactions (Fig. 37.20) (72). This valuable
OH information should serve as the starting point for the
C2H5
UDPGA
OH O
rational development of more potent and target-specific
glucuronyl transferase epipodophyllotoxins.
Dihydroxy acid Epipodophyllotoxins are cell cycle specific and have
O10-glucuronide metabolite (less active) their most devastating impact on cells in the S or early
metabolite (inactive) G2 phase. For this reason, doses are divided and admin-
istered over several days. Resistance is multifaceted and
UDPGA
glucuronyl transferase CYP3A4 involves downregulation of TopII, attenuation of enzy-
matic activity levels, development of novel DNA repair
HN CH3 NH2 mechanisms, and P-gpmediated cellular efflux.
CH2 CH2
HO O HO
N
O CHEMISTRY Structurally, the two marketed epipodophyl-
OH + N
N OH lotoxins, etoposide and teniposide, differ only in the
N
OH OH
nature of one -d-glucopyranosyl substituent (methyl or
C2 H5
C2H5 thienyl, respectively). Both are highly water insoluble,
OH O OH O but teniposides higher lipophilicity facilitates cellular
Dealkylated metabolites
uptake and results in a 10-fold enhancement of potency
(63). The need for solubility enhancers, such as polysor-
FIGURE 37.19 Topotecan metabolism. bate 80 (Tween, etoposide) or polyoxyethylated castor
oil (Cremophor EL, teniposide), in intravenous formu-
lations puts patients at risk for hypersensitivity reactions
Because both topotecan and irinotecan are metabo- that can manifest as hypotension and thrombophlebitis.
lized by CYP3A4, the potential for drugdrug interac- Epinephrine, antihistamines, and corticosteroids are
tions must be evaluated. Reduced clearance was noted often coadministered to minimize risk. A water-soluble
when azole antifungal agents and cyclosporine were phosphate ester analog of etoposide can be administered
coadministered with irinotecan, and accelerated clear- in standard aqueous vehicles, permitting higher doses
ance was observed when topotecan was coadministered than the oil-modified formulations would allow. The
with CYP3A4 inducers such as phenobarbital and pheny- phosphate ester is rapidly cleaved to the free alcohol in
toin. Unlike irinotecan, at the time of this writing, there the blood.
have been no published reports correlating the risk of
topotecan toxicity to UGT1A1 polymorphism. METABOLISM Epipodophyllotoxins are subject to meta-
bolic transformation before renal and nonrenal elimi-
Epipodophyllotoxins nation (Fig. 37.21). Etoposide is stable enough for oral
The epipodophyllotoxins (Fig. 37.17) are semisynthetic administration, although a dose approximately twice
glycosidic derivatives of podophyllotoxin, the major that of the intravenous formulation must be adminis-
component of the resinous podophyllin isolated from tered. Teniposide is more extensively metabolized, pre-
the dried roots of the American mandrake or mayapple sumably due to its enhanced ability to penetrate into
plant (Podophyllum peltatum). Although these compounds hepatocytes, and no oral dosage form is marketed. Both
are capable of binding to tubulin and inhibiting mito-
sis, their primary mechanism of antineoplastic action
is TopII poisoning, a mechanism that they share with H
anthracyclines (see antineoplastic antibiotics). TopII H3C O

O
has two distinct DNA-independent binding sites for the HO O
O
epipodophyllotoxins, one within the catalytic domain HO H
Asp737 O
and a second within the N-terminal adenosine triphos- (interacts with O
phate (ATP)-binding domain (70). Once bound, the catecholic analog) O
O
toxins stabilize the cleavable ternary drugenzymeDNA Tyr804
complex, stimulating DNA ligation but inhibiting reseal-
H3CO OCH3
ing. The DNA-topoisomerase fragments accumulate in OH
the cell, ultimately resulting in apoptosis. The RNA tran-
scription processes are also disrupted by the interaction Lys738 Gln784
of epipodophyllotoxins with TopII (63). The epipodo-
phyllotoxin binding site has recently been probed with FIGURE 37.20 Proposed etoposideTopII binding interactions.

H H and vomiting, most noticeable with the oral dosage form,

R O R O are generally mild.
O O
HO O HO O
O O
HO H OH HO H
O O SPECIFIC DRUGS (FIG. 37.17)
OH O Etoposide Etoposide is used in the treatment of small
O O
H O H O
cell lung cancer and in combination with other agents
in refractory testicular cancer. Both intravenous and oral
H3CO OCH3 H3CO OCH3
formulations are available. Oral bioavailability is concen-
OH OSO3
2 tration-dependent and runs approximately 50% for the
Hydroxy acid 50-mg capsule. Little first-pass metabolism is noted with
Sulfate conjugate
(major metabolite) the gelatin capsule dosage form. The drug is more than
Hydrolysis Sulfotransferase
96% protein bound, undergoes biphasic elimination, and
has a terminal half-life of 4 to 11 hours. Approximately
Etoposide 35% to 45% of a dose is eliminated via the kidneys, with
Teniposide
less than 6% excreted in feces. The drug should be
CYP3A4 H
used with caution in patients with renal or liver disease.
H
R
Specifically, doses should be decreased in patients with
R O O
O O
O
creatinine clearance of less than 50 mL/min or bilirubin
HO O HO O
O
HO H
levels of greater than 1.5 mg/dL, and the drug should
HO H
O O not be used in patients with bilirubin levels of greater
O O
O
than 3.1 mg/dL. Organoplatinum anticancer agents
O
H O
H O (e.g., cisplatin) decrease etoposide clearance, especially
in children. If used in combination, administration must
H3CO OH H3CO O be separated by at least 2 days.
OH O
Catechol metabolite Orthoquinone metabolite Teniposide Teniposide is used in combination with

other agents for the treatment of refractory childhood
FIGURE 37.21 Epipodophyllotoxin metabolism. acute lymphoblastic leukemia. Compared to etoposide, it
is more tightly protein bound (>99%), more extensively
metabolized, more slowly cleared (terminal half-life, 5
drugs undergo lactone hydrolysis to generate the inac- to 40 hours), and less dependent on renal elimination
tive hydroxy acid as the major metabolite, but the par- (10% to 21%). Exposure to heparin can cause teniposide
ent drugs can also be transformed by CYP3A4-catalyzed to precipitate, so lines must be thoroughly flushed before
O-demethylation and phase 2 glucuronide or sulfate and after teniposide administration. The drug can also
conjugation. Phase 2 metabolism accounts for between spontaneously precipitate, particularly if solutions are
5% and 22% of the dose. Clinically significant interac- overagitated, and patients receiving 24-hour infusions
tions between epipodophyllotoxins and CYP3A4 induc- should be monitored for blockage of access catheters.
ers, such as phenytoin, phenobarbital, and St. Johns Teniposide and etoposide are Category D teratogens
wort, have been documented, and coadministration can and, if at all possible, should not be used in women of
enhance antineoplastic drug clearance by as much as childbearing age.
77%. Conversely, CYP3A4 inhibitors, such as cyclospo-
rine or macrolide antibiotics, can decrease clearance,
leading to unwanted toxicity. Antibiotics
The catechol metabolite can oxidize to a reactive The antibiotic antineoplastics (Fig. 37.22) are a broad
orthoquinone, and both have been proposed to pro- category of natural or semisynthetic compounds that
mote topoisomerase-mediated DNA cleavage, poten- block DNA transcription by inhibiting enzymes critical to
tially enhancing the risk of the translocations that result the DNA replication process and/or by nicking and/or
in therapy-induced acute myeloid leukemia in children inducing point mutations in the DNA strand. Antibiotic
treated with these drugs. Epipodophyllotoxin-induced antineoplastics that interact directly with DNA first inter-
leukemia occurs in 2% to 12% of patients and is believed calate the double-stranded helix by inserting between the
to result from translocation of the MLL gene at chromo- base pairs and forming strong noncovalent interactions
some band 11q23. The mean latency period of 2 years is with DNA bases. The highly stabilized complex deforms
shorter than the 5- to 7-year latency for leukemia induced and uncoils the DNA, prohibiting proper replication. To
by DNA alkylators, and the drug-induced cancer is often bulldoze its way between the bonded DNA strands, a seg-
resistant to standard treatment (including bone mar- ment of the antibiotic must have the trigonal coplanar
row transplantation) (73). Other serious adverse effects geometry guaranteed by aromaticity.
include dose-limiting mucositis and myelosuppression, The antineoplastic anthracycline antibiotics func-
particularly leukopenia. Alopecia is common, and nausea tion as TopII poisons. Another mechanism of cytotoxic

O O O C (CH2)3-CH3 O
O OH O OH O OH O OH
C CH2-OH C CH2-OH C CH2 O C CH3
OH OH OH OH
CH3O O OH CH3O O OH CH3O O OH CH3O O OH O

O O O
O HO O O O
CH3 CH3 CH3 CH3
HO HO HO
NH3 NH3 HN C CF3 NH3
Cl Cl O Cl
Valrubicin Daunorubicin hydrochloride

Doxorubicin hydrochloride Epirubicin hydrochloride (Cerubidine)
(Adriamycin) (Ellence) (Valstar)
O H2 Sar Sar
O OH N O
C CH3 L-Pro L-MeVal L-Pro L-MeVal
OH O HN OH
D-Val D-Val O O CH2 O C NH2
O
OH L-Thr L-Thr H2N
O O OCH3
2 Cl
O OH O N NH2 CH3 N NH
O OH O HN OH
N O
CH3 H2 O O
HO
CH3 CH3
NH3
Cl
Idarubicin hydrochloride Mitoxantrone hydrochloride Dactinomycin Mitomycin

(Idamycin PFS) (Novantrone) (Cosmegen) (Mutamycin)
O NH2
NH2
H
N NH2 O
O N R
N N CH3 O
HO H
O N
H2N O NH N S
H3C HN O
N CH3 S
H HO CH3
O N
OH Bleomycin A2 R = SO42
N S(CH3)2
O N H 2
O H H
HO
OH Bleomycin B2 R= N NH2 SO42
HO O N
OH H 2
NH2
O
HO
O
NH2 Bleomycin sulfate (Blenoxane)
FIGURE 37.22 Anticancer antibiotics.
action, particularly for one antibiotic (bleomycin), is the O OH

O 14
generation of cytotoxic free radicals that cause single- 1 12 11 10 C R
13 Anthracyclinone aglycone
strand breaks in DNA. Another antibiotic (mitomycin) D C B A OH
is capable of alkylating DNA, a mechanism more com- 4 5 6
monly associated with the nitrogen mustard antineo- CH3O O OH O
O
plastics but that is predictable from the nucleophilic CH3 Protonated L-daunosamine
aziridine ring found within the structure of this antican- HO
cer agent. NH3
Anthracyclines and Anthracenediones

Anthracycline antineoplastic antibiotics are very closely MECHANISM OF ACTION Anthracycline-based antineoplas-
related to the tetracycline antibacterials. Structurally, tic agents act by poisoning TopII through the stabi-
they are glycosides and contain a sugar portion (l-dau- lization of the ternary drugenzymeDNA cleavable
nosamine) and a nonsugar organic portion. The non- complex. Like the topoisomerase poisons discussed
sugar portion of glycosides is generically referred to as earlier, they allow DNA to be cut and covalently linked
an aglycone. In anthracyclines, the aglycone moiety is to the conserved topoisomerase Tyr residue but inhibit
specifically called anthracyclinone or anthroquinone. the resealing reaction. The flat, aromatic portion of

the anthracyclinone ring system and the daunosamine moiety decreases DNA binding, it does not destroy it.
sugar bind to DNA, whereas the anthracyclinone A ring In fact, it has been stated that the antitumor activity of
is believed to bridge the gap between DNA and enzyme anthracyclines is related more to the proper positioning
(57,74). Since a small number of anthracycline-induced and stabilization of the drug within the cleavable ter-
DNA breaks can result in a high level of cell death, it has nary complex of drugtopoisomeraseDNA than to the
been hypothesized that the site of DNA cleavage, which actual affinity of the drug for the DNA (74,76).
contains an essential thymine-adenine (T-A) dinucleo- Resistance to anthracycline chemotherapy can be
tide, is particularly lethal to the cell (75). intrinsic or acquired. The major mechanisms through
which cancer cells fight back include compromised drug
CHEMISTRY DNA intercalation initiates the antineoplastic transport across cell membranes, active efflux via P-gp
action of the anthracyclines (58). Rings B, C, and D slide and MDR transporters, changes in tumor cell responsive-
between the two DNA strands, orienting the anthracycli- ness to apoptotic triggers, alterations in TopII expres-
none moiety in a perpendicular fashion relative to the long sion and activity, and augmented biochemical defenses
axis of DNA and stabilizing the complex through stacking against anthracycline-induced oxidative stress (78).
and other affinity-enhancing interactions. A recent study in Interestingly, some authors have shown that the poly-
which doxorubicin was docked in a modeled DNA post- phenol epigallocatechin-3-gallate (EGCG, found in
cleavage intercalation site proposed highly efficacious green tea) can inhibit cellular efflux of the anthracycline
H-bonds between top Ser740 and the C5 quinone oxygen doxorubicin (79,80) and sensitize doxorubicin-treated/
(ring C), top Thr744 and the C4-OCH3 (ring D), and a resistant human colon carcinoma cells (81). In addition
DNA thymine base and the C9-OH (ring A) (58). If pres- to the scientific evidence supporting the positive doxo-
ent, a C14-OH should H-bond with the carbonyl oxygen of a rubicinEGCG interaction, Sadzuka and colleagues (80)
DNA thymine base (Fig. 37.23). Interestingly, although the holistically state, We think that the intake of a favorite
C4-OCH3 helps hold drug to TopII enzyme, its removal beverage favors a positive mental attitude of the patient
increases antitumor activity by enhancing anthracyclinone and increases the efficacy of the chemotherapeutic index,
planarity (thereby facilitating intercalation) and by direct- and that this efficacy is useful for improving the quality of
ing the binding of the daunosamine sugar to stabilize the life on cancer chemotherapy.
inhibitory ternary cleavable complex (76).
The daunosamine sugar is known to bind in the minor OH
OH
groove of DNA at the DNA-topoisomerase interface and
subsequently orchestrate the DNA sequence specificity HO O OH
of the intercalation and overall DNA poisoning process OH
(58,74). Binding roles for the protonated 3-amino group
O C OH
have run the gamut from ionion paring with a DNA OH
O
phosphate to covalently linking to the C2-NH2 of guanine OH
via a formaldehyde methylene bridging unit (77). The Epigallocatechin 3-gallate
aforementioned molecular modeling study suggested (EGCG from Green tea)
that the cationic daunosamine amino group binds with
high affinity to the carbonyl oxygen of a DNA thymine CHEMICAL MECHANISM OF CARDIOTOXICITY An important
base when in the naturally occurring configuration. mechanism of use-limiting anthracycline cardiotoxicity
In the epimerized configuration, there is an increased involves the formation of cytotoxic free radicals. A free
distance between these two moieties and an unfavor- radical is a highly reactive species with an unpaired elec-
able steric interaction with other DNA residues. While tron. Of particular importance is the formation of super-
the loss or epimerization of the daunosamine 3-amino oxide radical anion (O2- ) and hydroxyl radical (OH),
both of which are formed via a one-electron reduction of
the anthracyclinone quinone (ring C) to hydroquinone
Thymine
by NADPH/CYP450 reductase. The mechanism by which
O
O OH
C CH2-OH
these reactive oxygen species (ROS) are generated is
shown in Figure 37.24.
Thr744 OH
When NADPH/CYP450 reductase reduces the qui-
O O OH none ring to a hydroquinone, superoxide radical anions
O Thymine
H3C O (O2- ) are generated. Superoxide radical anions react
CH3 to generate hydrogen peroxide (H2O2), a reaction that
Ser740 HO
NH3
requires protons and is catalyzed by the enzyme super-
oxide dismutase in a Cu2+-mediated process. The fate of
this hydrogen peroxide dictates the degree of cytotoxic-
Thymine
ity observed from the anthracycline.
FIGURE 37.23 Proposed interaction between doxorubicin, DNA, In the presence of the enzyme catalase, hydrogen per-
and topoisomerase II. oxide is rapidly converted to water and oxygen, which

OH OH
O radicals are generated within the heart, however, and can
C R
lead to acute, albeit reversible, cardiotoxicity. Cardiac tis-
D C B A OH sue is particularly vulnerable to free radical damage by
the anthracyclines because it does not contain signifi-
CH3O OH OH O
50 O cant amounts of catalase and other relevant cytoprotec-
O P4 CH3 tive enzymes (84). When hydrogen peroxide forms in
O OH CY
C R P H/ se HO the myocardium, it has no choice but to go down the
D t a
D A NA uc NH2
Fenton pathway. Cardiac toxicity is the major use-limiting
C B OH red
Anthracycline side effect of anthracycline use, but coadministration
CH3O O OH hydroquinone
O
O of dexrazoxane (an antioxidant and iron chelator) has
CH3 been shown to lower its incidence (85).
HO A role for nitric oxide metabolism, particularly nitric
NH2 O O
oxide synthase, in anthracycline-mediated cardiotoxicity
Superoxide radical anion has also been proposed (83,86). The reactive nitrogen
Anthracycline
species of greatest concern is peroxynitrite (ONOO), a
+2H /e Superoxide dismutase strong oxidant that shows no selectivity in its destruction
Cu2 of life-sustaining macromolecules.
Although the rate of quinone metabolism influences
Catalase Fe2
H2O + O2 H2O2 OH + OH + Fe3 the risk of acute anthracycline-induced cardiotoxicity,
Hydrogen Hydroxyl metabolism at C13 is believed to be responsible for the
peroxide radical more life-threatening chronic cardiotoxicity that some
FIGURE 37.24 Anthracycline-mediated free radical formation. patients experience. The C13-carbonyl is reduced via
a two-electron mechanism to a commonly less active
(87,88) or inactive (83) secondary alcohol via cytosolic
obviously are harmless chemicals as far as the body is con- aldoketoreductase enzymes (Fig. 37.25), and the larger
cerned. However, in the presence of ferrous ion (Fe2+), the R group, the slower this reaction and the longer the
hydrogen peroxide is converted into the highly toxic
hydroxyl radical through a process called the Fenton reac-
OH
tion. Hydroxyl radicals promote single-strand breaks in O OH
13 C R
DNA, which is therapeutically desirable to treat the uncon- Aldoketoreductase H
Anthracycline OH
trolled growth of cancer cells. Anthracycline anticancer
agents are also known to interfere with normal ferritin-iron CH3O O OH O
mobilization, resulting in iron accumulation (82). The O
CH3
anthracyclines chelate strongly with di- and trivalent cat-
HO
ions, including intracellular Fe2+, so the generation of cyto- NH2
toxic hydroxyl radicals after the initial NADPH/CYP450 OH
O OH C13-alcohol (rubicinol)
reductase reduction is essentially guaranteed. Hydroxide C R
H metabolite
anion and Fe3+ are also formed during the production of OH
hydroxyl radicals. Anthracyclineiron complexes (particu-
larly those involving Fe+3) can also spontaneously generate CH3O O OH OH
O-dealkylation
ROS without the aid of enzymatic catalysis (83).
Anthracycline aglycone
Fe2 OH
O OH
C R
H
O OH
O OH
C R
A HO O OH OH
D C B OH
CH3O O OH Conjugation
O (sulfation or
Fe2 glucuronidation)
O
CH3 OH
HO O OH
C R
H
NH3
OH
2
The generation of hydroxyl radicals inside the O3SO O OH OH
tumor cell could augment the antineoplastic effect of
Sulfate conjugate
the anthracyclines, but such generation is uncommon
at standard antineoplastic doses (75). These cytotoxic FIGURE 37.25 Anthracycline metabolism.

duration of antineoplastic action. The C13-substituents O

H
O O
H
O
found on most marketed anthracyclines include CH3 O C
HN N CH2 C N NH H 2N N CH2 C N NH2
(daunorubicin and idarubicin) and CH2OH (doxorubi- C O
H3C H3C
cin and epirubicin). Before excretion, anthracyclines are O O O O
further metabolized via hydrolytic or reductive deglyco-
Dexrazoxane ADR-925
sidation to their 7-hydroxy or 7-deoxy aglycones, respec-
tively, followed by O-dealkylation of the C4 methoxy ether
(if present) and conjugation with either glucuronic acid OTHER TOXICITIES In addition to cardiac toxicity, all anthra-
or sulfate. The aglycones may also have cardiotoxic prop- cycline antineoplastics can cause severe myelosuppres-
erties (83). sion (especially leukocytopenia) as well as moderate to
The secondary alcohol (rubicinol) metabolites severe nausea and vomiting, mucositis leading to hemor-
formed by aldoketoreductase concentrate in cardio- rhage and potentially fatal infection, and alopecia. Side
myocytes and induce a prolonged inhibition of calcium effects are dose-dependent. Most of the anthracyclines
loading, open a selective ion channel, inhibit Ca2+,Mg2+- are orally inactive and must be given by intravenous
ATPase leading to increased cytosolic levels of Ca2+ in injection. They are highly necrotic to skin and, if extrava-
the sarcoplasmic reticulum, and inhibit Na+,K+-ATPase sation occurs, can cause such severe blistering and ulcer-
action in the sarcolemma. Collectively, these cellular ation that skin excision, followed by plastic surgery, may
events can induce a chronic cardiomyopathy that pres- be indicated. The anthracyclines contain photosensitive
ents as severe congestive heart failure involving systolic phenolic groups that must be protected from light and
and diastolic dysfunction (82). As the rubicinol metabo- air. The highly conjugated structure imparts a reddish-
lites form a long-lived reservoir of cardiotoxic drug orange color to these compounds (implied in the name
within the myocardium, chronic anthracycline-induced rubicin), which is maintained when these compounds
congestive heart failure can manifest without warning are excreted in the urine. Patients should be warned that
years after therapy, and it is often unresponsive to ther- the reddish urine they will experience is not hemorrhagic
apeutic intervention (83). It has been estimated that but, rather, simply the result of the conjugated chemistry
more than half of the patients diagnosed with chronic of this class of drugs.
anthracycline-induced congestive heart failure will die The risk of serious or life-threatening adverse reac-
within 2 years (83). Elevated risk has been related to age tions can potentially outweigh the therapeutic benefits
(both very young and very old), genetic polymorphisms of anthracyclines in some patients, which has fueled the
impacting ROS production and/or anthracycline trans- search for biomarkers that will predict tumor responsive-
port, underlying cardiovascular disease, high cumulative ness to these powerful antineoplastic agents (90).
doses, and cyclophosphamide co-therapy. Females and
blacks appear to be at risk for increased incidence or SPECIFIC DRUGS (FIG. 37.22)
severity of drug-induced cardiomyopathy. Because tox- Doxorubicin Hydrochloride The C13 substituent of doxo-
icity is dose-dependent, patients with liver dysfunction rubicin is hydroxymethyl, which retards the action of
who cannot adequately metabolize and clear anthracy- cytosolic aldoketoreductase and slows the conversion
clines are also at risk. Dosage adjustments in patients to the less active and chronically cardiotoxic doxorubi-
with liver disease must be made to avoid life-threatening cinol. This contributes to the longer duration of action
toxicity. compared to analogs that have CH3 at this position (e.g.,
Although the acute and chronic phases of anthra- daunorubicin). Doxorubicin is highly lipophilic and con-
cycline-induced cardiomyopathy appear metabolically centrates in the liver, lymph nodes, muscle, bone mar-
distinct, a unifying hypothesis has recently been put row, fat, and skin. Elimination is triphasic, and the drug
forward to suggest that induction of ROS-mediated has a terminal half-life of 30 to 40 hours. The majority of
oxidative stress that characterizes acute cardiac toxicity an administered dose is excreted in the feces, approxi-
may upregulate aldoketoreductase, thereby facilitating mately half of it unchanged (83). Doxorubicin is used
the development of rubicinol-induced chronic toxic- either alone or in combination therapy to treat a wide
ity (83). As noted earlier, the pharmacotherapeutic range of neoplastic disorders, including hematologic
approach currently used to attenuate anthracycline- cancers and solid tumors in breast, ovary, stomach, blad-
induced cardiotoxicity is coadministration of dexrazox- der, and thyroid gland.
ane, an antioxidant and prodrug iron chelating agent. A liposomal formulation of doxorubicin, marketed as
Dexrazoxane readily enters cells and is hydrolyzed to Doxil, is used in the treatment of AIDS-related Kaposi
the active Fe2+ and Fe3+ chelating form (ADR-925). sarcoma and organoplatinum-resistant ovarian cancer.
Although the affinity of ADR-925 for iron surpasses that Liposomes are taken up selectively into tumor cells, pre-
of doxorubicin, iron-independent mechanisms for this sumably due to their persistence in the bloodstream and
cardioprotectant have also been proposed (83). This enhanced permeability of tumor vascular membranes. In
prodrug chelator can also be used to prevent serious liposomal form, the drug is protected against enzymes
tissue injury following accidental anthracycline extrava- that generate cardiotoxic free radicals and is less likely
sation (89). to concentrate in the heart (91). However, because this

form of the drug can still induce potentially fatal conges- The patient retains the drug in the bladder for 2 hours
tive heart failure, all precautions outlined for the use of and then voids the solution in the normal fashion.
doxorubicin are employed when the liposomal formula- Valrubicin is an active antineoplastic as adminis-
tion is used. The half-life of Doxil is extended to approxi- tered, although it does not function as a TopII poison.
mately 55 hours, and it is administered in doses ranging Rather, the intact drug inhibits the incorporation of
from 20 to 50 mg/m2 every 3 to 4 weeks. The area under nucleosides into DNA and RNA, which induces chro-
the curve of the liposomal formulation is approximately mosomal damage and cell cycle arrest (92). Despite
triple that of the free drug formulation. It is cleared more the fact that hydrolysis of the ester and trifluoroacet-
slowly than conventional doxorubicin and generates very amide can be readily envisioned, it is excreted essen-
little of the doxorubicinol metabolite. Significant side tially unchanged. Less than 1% of an administered
effects have occurred when the liposomal formulation is dose is absorbed systemically, so there is essentially no
erroneously dispensed, so pharmacists must be vigilant exposure to metabolizing enzymes. The reduced C13-
when interpreting therapeutic orders. alcoholic metabolite does not form to any appreciable
extent during the 2-hour treatment period. Therapy
Epirubicin Hydrochloride This stereoisomer of doxoru- is considered to be almost exclusively local, and there
bicin has the 4-hydroxy group of the daunosamine sugar is little risk for cardiac toxicity, bone marrow suppres-
oriented in the unnatural -position. However, this rel- sion, drugdrug interactions, or other side effects.
atively modest structural change has a large impact on Systemic exposure to the drug and its hydrolyzed (and
pharmacokinetic properties. Epirubicin is reduced to cardiotoxic) metabolites N-trifluoroacetyldoxorubicin
the C13 alcohol (epirubicinol) to a much lower (60%) and N-trifluoroacetyldoxorubicinol would, of course,
extent than doxorubicin, and it is not highly suscep- be greater in patients whose bladder wall integrity has
tible to ROS-generating one-electron oxidation. The been compromised by disease. These patients should
overall cardiotoxicity has been estimated at 30% lower not receive valrubicin. The most commonly reported
than doxorubicin, but the margin of safety is mitigated adverse reactions to valrubicin are abdominal pain,
somewhat by epirubicins greater propensity to accumu- urinary tract infection, hematuria, and dysuria. Some
late in myocardiocytes (83). The epirubicinol metabolite patients experience severe allergic reactions, most prob-
has an antitumor potency one-tenth that of the parent ably due to the Cremophor EL solubilizer that is notori-
drug and does not contribute significantly to the thera- ous for inducing hypersensitivity reactions. Unlike other
peutic action. Both parent drug and metabolite readily anthracyclines, valrubicin is not necrotic to skin.
undergo O-dealkylation/glucuronidation, resulting in a
shortened terminal half-life compared to doxorubicin. Daunorubicin Hydrochloride The absence of the OH
Cleavage to the aglycone will occur prior to elimination group at C14 in daunorubicin results in a faster conver-
(57,83). Although excretion is primarily biliary, dos- sion to the less active and chronically cardiotoxic C13-ol
age reduction in severe renal impairment, as well as in metabolite (daunorubicinol) compared to hydroxy-
hepatic dysfunction, is warranted. methyl-substituted anthracyclines like doxorubicin. The
Epirubicin is indicated for use in breast cancer, and 18.5-hour terminal half-life of daunorubicin is approxi-
the starting dose is 100 to 120 mg/m2 (compared to a mately half that of doxorubicin, and the terminal half-
starting dose of 60 to 75 mg/m2 for doxorubicin). The life of the daunorubicinol metabolite is 26.7 hours.
side effects and precautions are as outlined previously for Excretion is approximately 40% biliary and 25% urinary.
doxorubicin, although, as noted, there is a lower risk of Daunorubicin is administered intravenously at a dose of
serious myocardial toxicity or myelotoxicity. 45 mg/m2 for the treatment of lymphocytic and nonlym-
phocytic leukemia. The toxicity and side effect profile of
Valrubicin Chemically, valrubicin differs from its doxo- this anthracycline is similar to that of doxorubicin, and
rubicin parent by the addition of a C14-valerate ester and all previously identified precautions apply.
a 3-trifluoroacetamide moiety. The carbon-rich valerate The citrate salt of daunorubicin is marketed as a lipo-
is obviously lipophilic, and acylation of the daunosamine somal formulation, which promotes the use of this agent
amino group makes the 3-substituent nonionizable. in solid tumors. Like Doxil (the liposomal formulation of
Both of these structural changes promote a more rapid doxorubicin), DaunoXome is indicated for use in AIDS-
and extensive penetration into tumor cells. related Kaposi sarcoma and is administered intravenously
Valrubicin currently has orphan drug status in the at a dose of 40 mg/m2 every 2 weeks. The pharmacoki-
treatment of bacille Calmette-Gurinrefractory bladder netic profiles of Doxil and DaunoXome are similar.
cancer (the total patient population is 1,000 individu-
als) and is used in patients for whom surgical inter- Idarubicin Hydrochloride Idarubicin is the 4-desmethoxy
vention would result in high morbidity or death. It is analog of daunorubicin. The loss of the C4-ether flattens
administered directly into the bladder through a cath- the D ring, facilitating intercalation between DNA base
eter (intravesically). The lipophilic drug is water insol- pairs. In turn, this orients the daunosamine sugar in the
uble, but it dissolves in an aqueous vehicle that includes minor groove in a way that better stabilizes the ternary
polyethoxylated castor oil (Cremophor EL) and ethanol. complex between drug, DNA, and topoisomerase (76).

The loss of the 4-methoxy moiety also makes this com- In addition, the risk of ulceration and necrosis on
pound more lipophilic than either doxorubicin or dauno- extravasation, as well as of nonmarrow-related toxici-
rubicin. This results in a better penetration into tumor cells ties such as nausea, vomiting, mucositis, and alopecia, is
and an enhanced antineoplastic potency. Increased rates of significantly less than observed with true anthracyclines.
remission have been noted with the use of idarubicin com- There is a significant risk of bone marrow suppression,
pared to other anthracycline antineoplastic agents. Unlike however. The risk of myelosuppression increases with
its congeners, idarubicin shows significant oral bioavailabil- dose, but it can be observed even when low doses are
ity and is lipophilic enough to penetrate the bloodbrain used.
barrier. Currently, it is given only by the intravenous route Mitoxantrone excretion primarily is biliary. Both
and is not used in the treatment of brain cancer. Its primary the unchanged drug and inactive metabolites resulting
indication is in acute myeloid leukemia, and it is adminis- from N-dealkylation, deamination, and oxidation of the
tered in combination with other antileukemic drugs. resultant aldehyde to the carboxylic acid are observed.
Idarubicin is reduced by aldoketoreductases to idaru- Both arms of the structure can be metabolized, leading
bicinol which, unlike other rubicinols, is as active an anti- to mono- or dicarboxylic acid metabolites (Fig. 37.26),
tumor agent as the parent drug (88). Because there is no which are excreted as the glucuronide conjugate. The
aromatic methoxy group, there is no O-dealkylation to the conjugated metabolites are an intense, dark blue in color
C4-phenol. The major metabolite is free, unconjugated and will result in blue-green excrement. The whites of
idarubicinol. The half-lives of idarubicin and idarubicinol the eyes and, in some cases, the skin may also take on a
are 22 and 45 hours, respectively. Idarubicin is adminis- bluish cast.
tered intravenously at a dose of 10 to 12 mg/m2/day for Mitoxantrone is used in combination with other
3 to 4 days, and the idarubicinol metabolite can still be agents during the initial treatment of acute nonlympho-
found in therapeutic concentrations in the blood 8 days cytic leukemia and hormone-refractory prostate cancer.
after administration. Like other anthracyclines, excretion Mitoxantrone also decreases the rate of relapse and
primarily is fecal, with a lesser dependence on renal elimi- disease progression in patients with multiple sclerosis
nation. Some authors have shown that idarubicin is trans- (94). Although too toxic for use in patients with primary
ported into cardiac tissue via a saturable transporter and progressive disease, it is available for the treatment of
that the coadministration of methylxanthines (e.g., caf- chronic progressive, progressive relapsing, or deteriorat-
feine) can increase both myocardial drug concentrations ing relapsing-remitting multiple sclerosis.
and the risk of idarubicin-induced cardiotoxicity (93).
Miscellaneous Antibiotics (Fig. 37.22)
DACTINOMYCIN Dactinomycin has two pentapeptide lac-
Mitoxantrone Hydrochloride Chemically, mitoxantrone is tones attached to an aromatic (and, therefore, flat)
classified as an anthracenedione. The sugar moiety is miss- actinocin (or phenoxazinone) structure. It is capable
ing, but the cationic side-chain amino nitrogens could bind of intercalating DNA and binds preferably between
to the anionic phosphate residue of the DNA backbone in guanine and cytosine residues on a single DNA strand.
the same fashion that the cationic l-daunosamine amino This interaction results in DNA elongation and distor-
group of the true anthracyclines has been presumed to do. tion, commonly referred to as a point mutation. When
This molecule has the structural features needed to inter- sliding between adjacent DNA base pairs, the actinocin
calate DNA and inhibit TopII, but the enhanced stability orients itself perpendicular to the main DNA axis, allow-
of the quinone ring (possibly through an increased poten- ing the pentapeptide lactone units to bind to residues
tial for intramolecular hydrogen bonding) makes the ring in the minor groove of DNA through hydrophobic and
highly resistant to NADPH/CYP450 reductase. This limits
the formation of the highly toxic ROS. In addition, there is
no active cardiotoxic metabolite to induce chronic toxicity NH2
OH O HN
by disrupting the movement of myocardial cations. The
N-dealkylation
chance of cardiovascular toxicity from mitoxantrone is Mitoxantrone
significantly decreased, although patients who have been
OH O HN
previously treated with anthracycline antineoplastics may NH2
still be at risk. It is thought that any observed myocardial
Oxidative
toxicity may be operating through mechanisms other than Sites of potential deamination
glucuronide conjugation
the generation of cytotoxic radicals.
H H H H OH H
OH O HN OH O HN
N
O O N OH O O
Aldehyde
2Cl dehydrogenase
O O
OH O HN OH O HN
OH H
O O N OH
N
H H H H FIGURE 37.26 Mitoxantrone metabolism.

hydrogen bonds. An affinity-enhancing bond between O

O
O O C NH2
the threonine carbonyl oxygen and a protonated NQO1 reductase OH O C NH2
H 2N OCH3
C2-amino group of guanine also forms. Other hydrogen, NADPH/CYP450 H2N OCH3
reductase
hydrophobic, and -stacking interactions form between CH3 N NH
CH3 N NH
the lactone and DNA residues, particularly guanine and O
OH
cytosine.
The binding of the actinocin and polypeptide lac- Mitomycin O O Mitomycin hydroquinone
tone portions of dactinomycin to DNA is cooperative,
meaning that the binding of one unit facilitates the Fe 2+
binding of the other, most likely by promoting an opti- OH H2O2 CH3OH
mal orientation. This significantly enhances drug-DNA

O
affinity. The binding of dactinomycin to DNA, although OH
OH DNA O C NH2
noncovalent, is much stronger than that observed with H 2N DNA H2N
the anthracyclines. Drug dissociation from DNA is slow, DNA
leading to a pseudoirreversible effect. Dactinomycin CH3 N CH3 N NH
NH2
blocks gene transcription and translation processes, OH OH
and RNA polymerase is inhibited, resulting in a

decrease in de novo RNA (especially mRNA) and pro- Mitomycin-DNA adduct Indolohydroquinone
(cross-linked DNA) (intermediate)
tein synthesis. A recent study has also documented the
drugs ability to inhibit the polymerization of oligo- FIGURE 37.27 Mitomycin metabolism.
nucleotides containing the oncogenic c-Myc promoter
G-quadruplex sequence through direct binding to this
DNA segment (95). MITOMYCIN As shown in Figure 37.27, mitomycin is acti-
The p-benzoquinoneimine segment of dactinomycin vated through a two-electron bioreductive process using
renders the molecule vulnerable to NADPH/CYP450 NADPH/CYP450 reductase and/or NAD(P)H quinone
reductase. Free radicals can be generated, and addi- oxidoreductase 1 (NQO1 reductase), an enzyme exten-
tional single-strand DNA breaks can result. The loss of sively expressed in many neoplastic cells (9699). Through
either aromatic methyl group results in a loss of activity. these enzymes, the quinone ring of mitomycin is readily
The reason for this profound impact on pharmacologic reduced to the hydroquinone, generating superoxide
action and therapeutic utility is unknown. radicals in the process that ultimately will be converted to
cytotoxic hydroxyl radicals through the Fenton reaction.
As previously discussed, hydroxyl radicals induce single-
Sar Sar
Pentapeptide L-Pro L-Meval L-Pro L-MeVal strand breaks in DNA. Formation of the hydroquinone is
lactone D-Val O D-Val O followed by aromatization to the indole ring through the
L-Thr O O
L-Thr loss of methanol. Both the electrophilic aziridine ring and
N NH2
the + methylene group adjacent to the carbamate ester
Actinocin or phenoxazine are vulnerable to attack by DNA nucleophiles, such as the
ring system O O p-Benzoquinoneimine 2-NH2 group of guanine or the 4-NH2 group of cytosine,
CH3 CH3 and can conceivably result in cross-linked DNA and cell
death. The fact that mitomycin activating enzymes are
Dactinomycin
predominantly cytosolic has brought into question the
nuclear mechanisms long thought operational with this
Dactinomycin is used for the treatment of various solid antibiotic. A recent report has provided evidence for 18S
tumors and muscle-related cancers. It induces severe side rRNA as the true therapeutically relevant target of mito-
effects, and nausea and vomiting can be use-limiting. mycin. Through the inhibition of cytosolic rRNA, mito-
Myelosuppression is also common and, most often, is mycin would induce cell death through genome-wide
the dose-limiting toxic effect. The drug is usually given translational silencing (98).
by the intravenous route, but toxicity can be limited if Mitomycin is administered intravenously in the treat-
the tumor can be perfused with drug (assuming minimal ment of disseminated adenocarcinoma of the stomach or
distribution into the general circulation). Dactinomycin pancreas, and it has been used intravesically in superfi-
is a severe blistering agent, and extravasation can cause cial bladder cancer. Biotransformation pathways are satu-
irreversible and profound tissue damage. The side effects rable, and approximately 10% of an administered dose is
of radiation therapy are significantly exaggerated by the eliminated unchanged via the kidneys. Myelosuppression
concurrent use of dactinomycin. The drugs 36-hour is the major use-limiting side effect of this drug, which is
half-life is the result of a very high affinity for DNA, a slow to manifest but quite prolonged in duration. Severe
large volume of distribution, and minimal metabolic skin necrosis can occur on extravasation, and poten-
breakdown. Dactinomycin is photosensitive and must be tially fatal pulmonary toxicities have been noted as well.
protected from light. Mitomycin can induce hemolytic uremia accompanied

by irreversible renal dysfunction and thrombocytopenia, pKa 7.3 pKa 9.4

and the drug should not be administered to patients with
serum creatinine levels greater than 1.7 mg/dL. Severe O NH2
NH2
bronchospasm has also been noted in patients treated NH2 Bleomycin hydrase O
H
N NH2
with vinca alkaloids who are also receiving (or who have O
previously received) mitomycin. N N
O
CH3 O
NH3
Inactive carboxylate
HO H
O N metabolite
H2N O NH
BLEOMYCIN The commercially available bleomycin drug H3C HN O
product is a mixture of naturally occurring glycopeptides, N
H
CH3 HO CH3
N
predominantly bleomycin A2. Through DNA intercalation, O N S
the aromatic bithiazole ring system positions bleomycin OH
N
O O N
for DNA destruction via cytotoxic free radicals. The disac- HO H
OH S
charide, polyamine, imidazole, and pyrimidine structures HO O OH O
are very electron rich and readily chelate intracellular O R
HO
Fe2+. Once chelated, Fe2+ is oxidized to Fe3+ with a concom- O Bleomycin
itant reduction of bound oxygen. The ferric hydroperox- NH2
ide bleomycin complex is considered the cytotoxic form FIGURE 37.29 Bleomycin hydrase-mediated inactivation of bleo-
(100). Through the direct abstraction of a hydrogen atom mycin.
from 4 of deoxyribose, a free radical is generated that
subsequently decomposes to a highly electrophilic base
propenal that inactivates essential cellular proteins via Cys the -amino group, which normally interacts with DNA
alkylation (Fig. 37.28). Reduced GSH is proposed to serve in the un-ionized conjugate form. After hydrolysis, the
a protective role by acting as propenal scavenger and, until ratio of ionized to un-ionized forms of this critical amine
depleted, saves cellular proteins from alkylation (101). increases approximately 126-fold, destroying DNA affin-
Bleomycin is a natural product isolated from ity and leading to the loss of therapeutic action. Drug
Streptomyces verticillus. It is normally chelated with Cu2+, destruction via the bleomycin hydrase pathway is rapid,
which must be removed via catalytic reduction before and tumors will be resistant to bleomycin if they contain
marketing. This increases the cost of the drug, but it frees high concentrations of the enzyme. Conversely, tumors
up the critical bleomycin functional groups for chelation that are poor in bleomycin hydrase (e.g., squamous cell
with intracellular Fe2+. carcinoma) respond well to this agent.
The action of bleomycin is terminated through the Bleomycin hydrase is found in all tissues except skin
action of bleomycin hydrase, a cytosolic aminopeptidase and lung. Approximately 10% of patients who are admin-
that cleaves the terminal amide moiety to form the inac- istered bleomycin will experience potentially fatal pulmo-
tive carboxylate metabolite (Fig. 37.29). The metabolic nary fibrosis, which can occur during therapy or several
replacement of the electron-withdrawing amide with months following termination of therapy, often without
an electron-donating carboxylate increases the pKa of warning. The copper-complexing agent tetrathiomolyb-
date may reduce the risk of bleomycin-induced fibrosis
by inhibiting the action of copper-dependent inflamma-
tory cytokines (102). A recent report also supports the
4
BLM Fe
3
BLM Fe protective effect of inhibitors of the N-terminal catalytic
DNA
O O3PO-H2C
DNA site of angiotensin-converting enzyme (e.g., N-acetyl-Ser-
OOH O3PO-H2C
O O Asp-Lys-Pro or AcSDKP) (103). Erythema and hypertro-
4
phic modifications in skin are also common side effects
H abstraction H
OH H2O OH that manifest after 2 to 3 weeks of bleomycin therapy.
Bleomycin ferric DNA DNA radical Bleomycin is used intravenously in the palliative treat-
hydroperoxide ment of squamous cell head and neck cancers, testicu-
lar and other genital carcinomas, Hodgkins lymphoma,
and NHL. It is excreted via the kidneys, and serum con-
DNA O Cys SH DNA O centrations of active drug are increased in patients with
HC CH2 C H C CH C H renal disease. The elimination half-life can rise from 2 to
Protein H
S Cys Protein 4 hours to more than 20 hours in renal failure, result-
Base propenal ing in significant toxicity, especially pulmonary toxicity.
O
Dosage adjustments are warranted. Unlike many anti-
Reductive
cleavage H2C CH2 C H neoplastic agents, bleomycin does not suppress the bone
+ Damaged DNA
S Cys Protein
marrow, and it is often given in combination with com-
pounds that do so that the dose of all drugs can be opti-
Alkylated protein
mized. Nausea and vomiting are also relatively mild, but
FIGURE 37.28 Mechanism of bleomycin-induced DNA cleavage. approximately 1% of lymphoma patients who are treated

with bleomycin will experience an immediate or delayed The synthase enzyme is very large and contains a deep
severe idiosyncratic reaction that mimics anaphylaxis. pocket for the binding of both substrate and cofactor.
It may be illuminating to think of this binding pocket
Antimetabolites like a big cooking pot. Once the ingredients are added
MECHANISM OF ACTION The antineoplastic agents discussed (substrate and cofactor), the process of making the prod-
thus far have all damaged existing DNA (or, less com- uct (dTMP) can begin. The active site binding motifs for
monly, RNA) and inhibited its ability to replicate. The both substrate and cofactor are highly conserved among
antimetabolites, on the other hand, most commonly stop all thymidylate synthase enzymes, regardless of source
the de novo synthesis of DNA by inhibiting the formation (104). Whereas early studies on binding were conducted
of the nucleotides that make up these life-sustaining poly- with bacteria-derived synthases, the human enzyme
mers. We will see that the rate-limiting enzymes of nucle- (human thymidylate synthase [hTS]) has now been crys-
otide biosynthesis are often the primary targets for the tallized and some binding residues identified (105,106).
antimetabolites since inhibition of these key enzymes is As shown in Figure 37.31 (hTS sequence numbers
the most efficient way to shut down any biochemical reac- are given where known), Asp226 forms essential hydro-
tion sequence. Antimetabolites are also capable of inhibit- gen bonds with the dUMP pyrimidine 4-oxo and N3-H
ing other enzymes required in the biosynthesis of DNA, moieties, whereas His196 forms a hydrogen bond with
and many can arrest chain elongation by promoting the the pyrimidine 4-oxo moiety. The main-chain amide of
incorporation of false nucleotides into the growing DNA Asp218 forms a hydrogen bond with the pyrimidine 2-oxo
strand. moiety. Four arginine residues (50, 175, 176, and 215)
The antimetabolites serve as false substrates for criti- form electrostatic bonds with the anionic deoxyribose-
cal nucleotide biosynthesis enzymes. These enzyme 5-phosphate, and Tyr (H-donor) and histidine (His)
inhibitors are structurally dolled up to look like a super (H-acceptor) residues form hydrogen bonds with the
attractive version of the normal (endogenous) substrate. deoxyribose 3-OH. As noted in the dTMP synthesis path-
Speaking anthropomorphically, through a form of chem- way (Fig. 37.30), Cys195 forms a transient covalent bond
ical entrapment, they entice the enzymes to choose them with pyrimidine C6.
over the endogenous substrate and, once they do, the The glutamate tail of 5,10-methylene-THF cofactor
antimetabolites bind them irreversibly or pseudoirrevers- binds to Phe80, Lys, and His residues of the synthase,
ibly. If the building block nucleotides cannot be synthe- whereas Leu221, Ile108, Phe80, and Phe225 interact
sized, then DNA synthesis (and tumor growth) is stopped with the p-aminobenzoic acid component of the folate.
dead in its tracks. If tumor growth is arrested, then Asp218, Leu221, and Phe225 are known to interact
metastasis slows, and the patient has a fighting chance with the pteridine portion of the cofactor (Fig. 37.31)
for remission and/or cure. (105107).
Many antimetabolite antineoplastics are categorized The binding of both substrate and cofactor promotes
by the class of nucleotide they inhibit. Purine antago- a conformational change in the synthase protein and
nists inhibit the synthesis of the purine-based nucleo- causes the N-terminal portion of the synthase to change
tides adenosine monophosphate (AMP) and guanosine its location, which covers the opening of the binding
monophosphate (GMP), and the pyrimidine antagonists pot like a big lid. The conformational change positions
stop the production of the pyrimidine-based nucleotides, the pteridine ring of the folate cofactor face to face
primarily deoxythymidine monophosphate (dTMP). with the dUMP substrate, permitting the ring stacking
that properly orients all key functional groups for the
Pyrimidine Antagonists: dTMP Synthesis Inhibitors reaction to come (106).
DTMP BIOSYNTHESIS Looked at simply, dTMP is produced
via C5-methylation of deoxyuridine monophosphate CHEMISTRY The C6 position of the dUMP substrate is
(dUMP). The rate-limiting enzyme of the dTMP synthetic surrounded by electron-withdrawing nitrogen and
pathway is the sulfhydryl-containing thymidylate syn- oxygen atoms, leaving it highly electrophilic (+) and
thase, with 5,10-methylenetetrahydrofolate (5,10-methy- ready to be attacked by the nucleophilic Cys195 of the
lene-THF) serving as the methyl-donating cofactor. All synthase. The Cys sulfhydryl (SH) group launches an
dTMP synthesis inhibitors will inhibit thymidylate syn- intermolecular nucleophilic attack, forming a new cova-
thase either directly or indirectly, and this will result in lent bond between the sulfur and C6 of the substrate
a thymineless death in actively dividing cells. Without (step 1). The bond that breaks in response to this attack
dTMP and its deoxythymidine triphosphate metabolite, is the 5,6-double bond of dUMP, which attacks the methy-
DNA will fragment, and the cell will die. lene group of the cofactor (step 2). With the release of
To understand how an antimetabolite inhibits a bio- the N10 nitrogen, the cofactor imidazolidine ring breaks
chemical pathway, we must first understand completely (step 3). Taken together, steps 1 to 3 generate a ternary
how the pathway normally functions. A quick look at the complex of enzyme, substrate, and cofactor (Fig. 37.30).
dTMP synthesis pathway (Fig. 37.30) will confirm that A series of reactions involving bond breaking and
our simple methylation reaction is comprised of several bond making are shown in Figure 37.30, leading to
important steps, each of which is analyzed in turn below. formation of dTMP, 7,8-dihydrofolate (7,8-DHF), and

H
Proton abstracted NH2 N N Release of hydride
by cofactor N10 H
NH
4 N
O NH
O H CH2 COOH
H
N (CH2)2
HN
O COO
O O N
O H2C
O P O S Cys
H OH
Thymidylate Synthase
NH2 N N HO
O NH Ternary complex
N
5 H 5 (enzyme-substrate-cofactor) H
HN O N 10
COOH O
2 H
O O N 6 3 N (CH2)2 CH2
HN
O P O H2C
O 1
OH O COO O O N
S Cys O P O H2C
O S Cys
HO H OH
dUMP TS
HO
HS Cys
SHMT
pyridoxyl Thymidylate Synthase
phosphate
(Regenerated enzyme)
H H O
NH2 N N NH2 N N CH3
HN
NH NH O
N N O N
DHFR + O P O H 2C
O H NH O NH O
OH
NADPH
HO
H H
O N C (CH2)2-COOH O N C (CH2)2-COOH
H H
COO COO
THF 7,8-DHF dTMP
FIGURE 37.30 Synthesis of deoxythymidine monophosphate (dTMP).
regenerated thymidylate synthase. The C5-H abstraction key to the cell-killing action of this drug. The C6 position
by N10 of the cofactor (step 4) is essential for synthesis of the false substrate is significantly more electrophilic
of dTMP. To complete the biochemical cycle, 7,8-DHF than normal due to the strong electron-withdrawing
must be reduced to tetrahydrofolate (THF) via dihydro- effect of the C5 fluorine. This greatly increases the rate
folate reductase (DHFR) using NADPH. Finally, THF is of attack by Cys195, resulting in a very fast formation of a
converted to 5,10-methylene-THF through the action of fluorinated ternary complex (Fig. 37.34). The small size
serine hydroxymethyltransferase and vitamin B6. of the fluorine atom assures no steric hindrance to the
With the enzyme and cofactor both regenerated and formation of this false complex.
with plenty of dUMP stored in cellular pools, the cell is The next step in the pathway required the abstraction
ready to synthesize another molecule of dTMP. This hap- of the C5-H (as proton) by N10 of the cofactor, but this
pens at a regular pace in healthy cells and at an uncon- is no longer possible. Not only is the C5-fluorine bond
trolled rate in tumor cells. stable to cleavage, the fluorine atom and N10 would repel
one another because they are both electron rich. The
SPECIFIC DRUGS: PYRIMIDINE ANALOGS (FIG. 37.32) false ternary complex cannot break down, no product is
Fluorouracil To bind to thymidylate synthase, this flu- formed, no cofactor is released, and most importantly,
orinated pyrimidine prodrug must be converted to its the rate-limiting enzyme (thymidylate synthase) is not
deoxyribonucleotide form (Fig. 37.33). The active form regenerated. With thymidylate synthase directly and irre-
of fluorouracil differs from the endogenous substrate only versibly inhibited, dTMP can no longer be synthesized
by the presence of the 5-fluoro group, which holds the and the cell will die.

Asn 226 His 196 phosphorylation to the same active 5-fluoro-dUMP struc-
O
ture generated in the multistep biotransformation of flu-
Arg 50
Asp218 H orouracil (Fig. 37.33). It is given by intra-arterial infusion
N
for the palliative treatment of GI adenocarcinoma that
O N has metastasized to the liver and that cannot be managed
Arg 215 HO3PO-CH2
O Cys 195 surgically. Because floxuridine does not generate fluoro-
uracil, its kinetic profile is not impacted by DPD pharma-
Arg 176'
Arg 175'
cogenetic status.
OH
Tyr His
Capecitabine Although capecitabine is a carbamylated
dUMP
analog of cytidine, the drug actually is another 5-fluoro-
H dUMP prodrug (Fig. 37.36). Given orally, it is extensively
NH2 N N metabolized to fluorouracil, which is then converted
Asp 218 NH to the active fluorinated deoxyribonucleotide as previ-
N
O N
ously described. Thymidine phosphorylase, an enzyme
involved in this biotransformation, is much more active
Phe 225
in tumors than in normal tissue, which improves the
Leu 221
tumor-selective generation of fluorouracil. Levels of
H
Ile 108 O
C N (CH2)2-COOH active drug in the tumor can be up to 3.5-fold higher
COO than in surrounding tissue, leading to a lower incidence
Phe 80 His of side effects compared to fluorouracil therapy (110).
Lys Because capecitabine is biotransformed to fluorouracil,
it follows the same catabolic and elimination pathways
5,10-Methylene-THF reported for fluorouracil (Figs. 37.33 and 37.35). Doses
FIGURE 37.31 dUMP and 5,10-methylene-THF binding to thymi- should be attenuated in moderate to severe renal impair-
dylate synthase. ment, and the caution relative to the augmented risk of
toxicity in patients with dihydropyrimidine dehydroge-
nase deficiency applies.
Fluorouracil is administered intravenously in the pal- Capecitabine is indicated for use as first-line therapy
liative treatment of colorectal, breast, stomach, and pan- in patients with colorectal cancer. It is also used alone
creatic cancers. Patients are treated for 4 consecutive or in combination with docetaxel in patients with met-
days, followed by treatment on odd-numbered days up astatic breast cancer who have experienced disease
to a maximum of 12 days. Fluorouracil is rapidly cleared progression or recurrence after anthracycline therapy.
from the bloodstream, and although up to 20% of a dose Given twice daily in tablet form, the total daily dose is
is excreted unchanged in the urine, most undergoes calculated based on patient body surface area and is
hepatic catabolism via a series of enzymes that includes taken 30 minutes after eating to avoid food-induced
the polymorphic dihydropyrimidine dehydrogenase decreases in absorption. In addition to bone marrow
(DPD) (Fig. 37.35). Patients who are genetically defi- suppression, nausea, and vomiting, the drug can induce
cient in this enzyme (5% of the population) will experi- severe diarrhea and a potentially disabling disorder
ence a more pronounced effect from this drug and are at termed hand-and-foot syndrome (palmar-plantar
significant risk for use-limiting or life-threatening toxic- erythrodysesthesia).
ity unless doses are appropriately adjusted (108). It has Capecitabine inhibits CYP2C9 and, along with com-
been estimated that between 40% and 60% of patients petition for serum protein binding sites, results in
who experience severe toxicity from fluorouracil are defi- clinically significant drugdrug interactions with both
cient in DPD (109). The incidence of DPD deficiency in warfarin and phenytoin. The interaction with warfa-
African Americans is threefold higher than in Caucasians, rin can result in potentially fatal bleeding episodes,
and black women have a threefold higher incidence of which can appear within days of combination therapy
DPD deficiency than black men (109). In patients with or be delayed up to 1 month after discontinuation of
normal DPD activity, dosage adjustments are usually not capecitabine therapy.
required in hepatic or renal dysfunction. Major toxicities
are related to bone marrow depression, stomatitis/esoph- SPECIFIC DRUGS: ANTIFOLATES (FIG. 37.32)
agopharyngitis, and potential GI ulceration. Nausea and Methotrexate Methotrexate is a folic acid antagonist
vomiting are common. Solutions of fluorouracil are light structurally designed to compete successfully with 7,8-
sensitive, but discolored products that have been prop- DHF for the DHFR enzyme. The direct inhibition of
erly stored and protected from light are still safe to use. DHFR causes cellular levels of 7,8-DHF to build up, which
in turn results in feedback (indirect) inhibition of thymi-
Floxuridine This deoxyribonucleoside prodrug is dylate synthase. Methotrexate is also effective in inhibit-
bioconverted via 2-deoxyuridine kinasemediated ing glycine amide ribonucleotide (GAR) transformylase

Pyrimidine antagonists: Purine antagonists:

O
O O HN C O (CH2)4-CH3
F F F
HN HN N SH SH
N N N N
O N O N O N
H HO H2C H3C
O O N N H2N N N
H H
HO HO OH Mercaptopurine Thioguanine
Fluorouracil Floxuridine Capecitabine (Purinethol) (Tabloid)
(Adrucil) (FUDR) (Xeloda)
Folate antagonists:
H2N N N O
H
N COOH HN N (CH2)2-COO
N O
NH2 N C N (CH2)2-COOH H2N N N O COO 2 Na
H3C H H
Methotrexate (Trexall) Pemetrexed disodium (Alimta)
H2N N N C CH
O COOH
H
N C N CH
N
CH2CH2COOH
NH2
Pralatrexate (Folotyn)
DNA polymerase and chain elongation inhibitors:
NH2 NH2 NH2 NH2 NH2

H N N N
N Cl N N N N
O N O N O F N N Cl N N Cl N N
HO-CH2 O HO-CH2 O HO P O CH2 O HO CH2 O HO CH2 O
HO F OH HO F
HO HO F HO HO HO
Cytarabine Gemcitabine Fludarabine phosphate Cladribine Clofarabine

(Tarabine PFS, hydrochloride (Fludara) (Leustatin) (Clolar)
DepoCyt) (Gemzar)
Miscellaneous antimetabolites:
H OH
N O
HN OH
H2N N
N N H
HOCH2
O
Hydroxyurea
(Hydrea)
OH
Pentostatin
(Nipent)
FIGURE 37.32 Antimetabolites.
(see Fig. 37.38), a key enzyme in the synthesis of purine (Fig. 37.37). N5 is the strongest base in the DHF structure,
nucleotides. in part due to attenuating the impact of the C4 carbonyl on
Methotrexates C4-NH2 substituent, along with its lack electron density around N1. Additional affinity-enhancing
of a 7,8-double bond, hold the key to its DHFR-inhibiting interactions between enzyme and substrate have also been
action. It has been proposed that the N5 position of DHF identified (112,113), and once bound, the substrates
is protonated by Glu30 of DHFR (111) and, in cationic 5,6-double bond is positioned close to the NADPH cofac-
form, binds to DHFR Asp27 through an electrostatic bond tor so that the transfer of hydride can proceed.

1 H 8 O
H2N N N 5 F
7 H
HN
HN COO NH2 N N
4 N5 O O N 6 H
O HN C N (CH2)2-COOH HO3PO H2C NH
H O 2 N
10
O N
COOH
7,8-Dihydrofolate HO 1 H
N (CH2)2
1 8 5-F-dUMP O COO
H2N N N 7 (false substrate)
S Cys 5,10 MethyleneTHF
N COO H (cofactor)
4 N5 O
NH2 N C N (CH2)2-COOH Thymidylate Synthase
10 H (enzyme)
CH3
FAST
Methotrexate Glutamate tail

5-F cannot be H
abstracted by NH2 N N
In contrast, the C4-NH2 substituent of methotrex- N10 of cofactor
H
ate enriches electron density at N1 through -electron NH
N
donation, increasing its basic character between 10- and O NH
1,000-fold and promoting protonation by Glu30 at the O F CH2
H
COOH
N (CH2)2
expense of N5. Because N1 and N5 are across the pteri- HN
dine ring from one another, the interaction of N1 with O COO
O N
the DHFR Asp27 will effectively stand the false substrate H2C
O
O O S Cys
O P
OH HO
O
O
F
F HN
HN Orotate phopho- Stable fluorinated ternary complex
O N
O N ribosyltransferase HO3PO H2C
H O FIGURE 37.34 Mechanism of action of fluorouracil.
HO OH
Fluorouracil 5-Fluorouridine
on its head relative to the orientation of 7,8-DHF
(Prodrug) monophosphate (Fig. 37.37) (113,114). With the 5,6-double bond of
(5-FUMP) methotrexate 180 degrees away from the bound NADPH
cofactor and stabilized by the fully aromatic pteridine
UMP kinase ring, the possibility for reduction is eliminated (113).
The DHFR enzyme will be pseudoirreversibly bound to
O O a molecule it cannot reduce, which ties up the DHFR
HN
F Ribonucleotide
HN
F enzyme and prevents the conversion of DHF to THF. In
reductase turn, this halts the synthesis of the 5,10-methylene-THF
O N O N
H2O6P2O H2C H2O6P2O H2C cofactor required for dTMP biosynthesis and causes feed-
O O
back inhibition of the thymidylate synthase enzyme. The
cell will die a thymineless death.
HO HO OH
Methotrexate is given orally in the treatment of
5-Fluorodeoxyuridine 5-Fluorouridine breast, head and neck, and various lung cancers as well
diphosphate (5-F-dUDP) diphosphate (5-FUDP)
as in NHL. The sodium salt form is also marketed for
Phosphatase
intravenous, intramuscular, intra-arterial, or intrathe-
cal injection. Oral absorption is dose-dependent and
O O peaks at 80 mg/m2 due to site saturation. The mono-
HN
F
2'-Deoxyuridine HN
F glutamate tail of methotrexate permits active transport
into cells via a reduced folate carrier (RFC1), which
O N kinase O N
HO3PO H2C HO H2C predominates at serum concentration levels lower than
O O
100 mol/L. Methotrexate undergoes intracellular folyl
polyglutamate synthase (FPGS)-catalyzed polyglutama-
HO HO
tion, which adds several anionic carboxylate groups to
5-Fluorodeoxyuridine Floxuridine the molecule and traps the drug at the site of action.
monophosphate (5-F-dUMP) (Prodrug) Polyglutamation is more efficient in tumor cells than in
(Active form)
healthy cells, which promotes the selective toxicity of this
FIGURE 37.33 Activation of fluorouracil and floxuridine. drug. The polyglutamated drug will be hydrolyzed back

O O H
H2N N N
F F NADPH
HN Dihydropyrimidine HN 5 6
HN 4 COOH
N+ O
O N dehydrogenase O N
H H O H HN C N (CH2)2-COOH
H
Fluorouracil 5-Fluoro-5,6- -
dihydrouracil 7,8-Dihydrofolate
Asp27 (properly oriented)
Dihydropyrimidinase
H3C H
O -ureidopropionase O O NH2 5 N C N (CH2)2-COOH
N O
H2N OH H2N N OH N 6 COOH
F
H
F
1 NADPH
H 2N N + N
O
-Fluoro--alanine -Fluorouridopropionic H
H2N OH acid
-
Methotrexate
Asp27
(misoriented)
NH3 + CO2
FIGURE 37.37 Misorientation of methotrexate at DHFR.
FIGURE 37.35 Fluorouracil metabolism.
to the parent structure before renal elimination. Up to and pleural effusions and/or when renal excretion is
90% of an administered dose of methotrexate is excreted impaired by kidney disease. When used in high doses,
unchanged in the urine within 24 hours. methotrexate and its 7-hydroxymetabolite (which has
Methotrexate toxicity occurs with high doses if a three- to fivefold lower water solubility) can precipi-
third space fluids allow drug to accumulate in ascites tate in the renal tubule, causing damaging crystalluria.
Methotrexate-induced lung disease is a particularly
critical problem because it arises at any time and at any
O
HN C O (CH2)4-CH3 NH2 dose and can be fatal. Methotrexate use also precipitates
F N
F severe GI side effects, including ulcerative stomatitis
N
and hemorrhagic enteritis, leading to intestinal perfora-
O N
O N
H3C tion. Potentially fatal skin reactions are a risk as well. As
H3C O
O Carboxyesterase a Category X teratogen, this drug should not be given
to women who are pregnant or planning to become
HO OH
HO OH pregnant.
Capecitabine 5'-Deoxy-5-fluorocytidine If severe methotrexate toxicity occurs, reduced
(5'-DFCR)
folate replacement therapy with 5-formyltetrahydrofo-
Cytidine deaminase
late (leucovorin) must be initiated as soon as possible.
Leucovorin generates the folate cofactors needed by
DHFR and GAR transformylase to ensure the contin-
O O
F F
ued synthesis of pyrimidine and purine nucleotides
HN HN in healthy cells. Leucovorin rescue therapy is often
Thymidine
O N
phosphorylase
O N given as prophylaxis after high-dose methotrexate
H H3C
O therapy.
Fluorouracil
HO OH H
H2N N N
1) Orotate phospho- 5'-Deoxy-5-fluorouridine
ribosyltransferase HN COO
(5'-DFUR) N O
2) UMP kinase
3) Ribonucleotide reductase O HN C N (CH2)2-COOH
O H H
4) Phosphatase
O 5-Formyltetrahydrofolate
F (Leucovorin)
HN
O N 5-F-dUMP
HO3PO H2C
O
Cancer cells can become resistant to methotrexate
over time. Acquired resistance mechanisms include
increased DHFR expression, impaired transport,
HO
active cellular efflux, and/or attenuated intracellular
FIGURE 37.36 Capecitabine activation. polyglutamation.

Pemetrexed Disodium Pemetrexed is a novel multitar- Pralatrexate The only structural difference between
get antifolate administered by the intravenous route for pralatrexate and methotrexate is in the area of N10; pra-
the treatment of advanced or metastatic nonsquamous latrexate is a 10-deaza analog where the carbon atom
non-small cell lung cancer (115) and in combination replacing N10 has been substituted with a triple bond-con-
with cisplatin in malignant pleural mesothelioma. Like taining propargyl group. This structural alteration results
methotrexate, it is actively transported into tumor cells in a significantly enhanced tumor cell uptake via RFC1
via RFC1. Pemetrexed has a higher affinity for FPGS than and FPGS-mediated polyglutamation compared to meth-
methotrexate, so more polyglutamated drug is generated otrexate and pemetrexed without compromising affinity
(and trapped) inside the cancer cell. Tetra- and pentaglu- for target enzymes (122,123). The rate of active transport
tamates predominate. Both mono- and polyglutamated of pralatrexate into tumor cells by RFC1 has been mea-
forms of pemetrexed are capable of inhibiting DHFR, sured at approximately 12 to 14 times that of methotrex-
and they do so with comparable activity (116,117). Unlike ate, and a 10-fold higher FPGS polyglutamation efficacy
methotrexate, pemetrexed does not distribute centrally has been estimated (124,125). This translates to more
to any significant extent (117). active drug inside the tumor cell for a longer period of
In addition to DHFR, polyglutamated pemetrexed (but time. Pralatrexate is excreted intact in the urine.
not the monoglutamated parent) binds tightly to thymi- Unlike pemetrexed, which is also more extensively
dylate synthase and GAR transformylase (116,118,119). polyglutamated than methotrexate, pralatrexates pri-
Since intracellular polyglutamation of pemetrexed is so effi- mary antineoplastic enzymatic target is DHFR. Although
cient, this drug realizes a significant portion of its potent anti- it interacts with and inhibits the isolated DHFR enzyme 2-
cancer activity through the inhibition of these two enzymes. to 3-fold less vigorously than methotrexate (Ki apparent =
In fact, thymidylate synthase is considered its primary tar- 26 and 45 nmol/L, respectively), the cellular influx and
get. Fortunately, the affinities of the polyglutamated forms polyglutamation first-order rate constants (Vmax/Km) are
of pemetrexed for this enzyme are higher than that of the 12- and 10-fold greater, respectively (126). Higher concen-
monoglutamate parent form, so efficacy is not sacrificed for trations of active polyglutamated drug trapped within the
enhanced localization at the site of action. Pemetrexed is cell provide a more potent DHFR inhibitory effect com-
often used in combination with the organometallic cisplatin pared to methotrexate and a greater antitumor response
(116). A synergistic effect with gemcitabine (a DNA poly- than either methotrexate or pemetrexed (123,126).
merase inhibitor) in the treatment of lung cancer patients Pralatrexate dosing is based on body surface area
has also been noted as long as gemcitabine is administered in order to standardize exposure to active drug. Some
immediately prior to the antifolate (117). T-cell lymphoma patients treated with pralatrexate have
Patients on pemetrexed must take folic acid (commonly achieved complete remission (124). In addition to T-cell
400 mg daily) and vitamin B12 (1 g on an established lymphoma (127), pralatrexate might eventually find use in
schedule) to reduce the risk of bone marrow suppres- the treatment of non-small cell lung cancer and, in com-
sion (neutropenia, thrombocytopenia, and anemia) and bination with the DNA polymerase inhibitor gemcitabine,
use-limiting GI side effects like mucositis and stomatitis. in NHL. When used in combination with gemcitabine, the
Pretreatment with corticosteroids can reduce the risk of synergistic apoptotic effect is maximized when the antifo-
drug-induced skin rash. Antiemetic therapy to proactively late is administered before the polymerase inhibitor (126).
combat drug-induced nausea and vomiting is also war- Pralatrexate is not effective against B-cell lymphoma (125).
ranted (117). Pemetrexed has a half-life of 3.5 hours and As with other antifolates, patients on pralatrexate should
is excreted primarily unchanged via the kidneys. receive daily folic acid supplementation and vitamin B12 to
Resistance to pemetrexed is mediated through a reduce the risk of mucositis/stomatitis and bone marrow
decrease in FPGS activity, enhanced hydrolysis of peme- suppression. Whereas the latter adverse effect is viewed as
trexed polyglutamates via -glutamyl hydrolase enzymes, a minor risk (126), mucositis has been termed the major
and upregulation of the thymidylate synthase target. dose-limiting adverse reaction, particularly in patients with
Significant cross-resistance has been noted between high levels of methylmalonic acid (128). Unlike metho-
pemetrexed and other pyrimidine and folate antagonists trexate, acquired resistance to pralatrexate is believed to
(116,120). A recent study has shown that pharmacogenetic be more highly dependent on a reduced expression of
differences in ATP-binding cassette (ABC) C11 transport- RFC1 than on an increased expression of DHFR (129).
ers may be an important predictor of sensitivity to peme-
trexed chemotherapy (121). In the ABCC11 SNP 538G>A, Purine Antagonists: Amidophosphoribosyl Transferase
the A/A variant (unlike the G/G or G/A) does not promote Inhibitors
pemetrexed efflux from the cancer cell. ABCC11 genotype AMP AND GMP BIOSYNTHESIS Purine antagonists inhibit the
also impacts the nature of earwax, and it has been noted de novo biosynthesis of AMP and GMP. The rate-limiting
that East Asians (80% to 95% of whom express the A/A enzyme in the synthesis of these purine nucleotides is ami-
variant and have dry earwax) are particularly responsive dophosphoribosyl transferase (also known as phosphori-
to pemetrexedcisplatin chemotherapy. Patients express- bosylpyrophosphate amido transferase), which is a major
ing the other ABCC11 variants would be at risk for peme- target for one of the two thiol-containing purine antican-
trexed resistance due to excessive drug efflux. cer antimetabolites on the U.S. market (mercaptopurine).

H
Glycine O NH2 N O
Glutamine H2O3PO H2C NH2 H2O3PO H2C
H2O3PO H2C
O H O O HN C GAR transformylase H
O NH
H 2+ H 10-Formyl
OP2O6H3 Amidophospho- ATP, Mg H2O3PO H2C
THF O
ribosyl transferase, HO OH HO OH
HO OH
Mg2+ H
5-Phosphoribosyl 5-Phosphoribosyl Glycine amide ribo- HO OH
pyrophosphate amine nucleotide (GAR) Formylglycine
ribonucleotide
O H
HO2C N N O
H2N N N
H Glutamine
H2N N Aspartate H2N N CO2 H2N N HN NH
H2O3PO H2C H2O3PO H2C H2O3PO H2C ATP H2O3PO H2C
O O O O
2+
H H H + 2+ H ATP, Mg
K , Mg
HO OH HO OH HO OH HO OH
O O O
O Glutamine
N HN N HN N
10-FormylTHF H2N N HN Oxygenase
H
O C N N
NH N N O N H2N N
N H
H2O3PO H2C H2O H2O3PO H2C O H2O3PO H2C O
O H2O3PO H2C O
H H H H
HO OH HO OH HO O HO OH
H
Inosinic Acid Xanthylic Guanylic acid
Aspartate acid (GMP)
NH2
N N
N N
H2O3PO H2C O
H
HO OH
Adenylic
acid (AMP)
FIGURE 37.38 Biosynthesis of purine nucleotides.
The pathway outlining the synthesis of AMP and GMP and GMP biosynthesis. A second mechanism of antineo-
is provided in Figure 37.38. It is important to recognize plastic activity for mercaptopurine (and the predominant
that the rate-limiting step is the first of the pathway; if that mechanism for thioguanine) involves the incorporation
step is inhibited, no other step can proceed. Since the of di- and triphosphate deoxy- and ribonucleotides gen-
rate-limiting transferase enzyme works on a phosphory- erated within the tumor cell into DNA and RNA, respec-
lated ribose substrate, no enzyme in the sequence will tively (130). This illicit substitution inhibits further
function without its presence. The formylation reaction elongation of the strands and promotes apoptosis.
catalyzed by GAR transformylase requires the methyl- Thiopurines are metabolized by S-methylation via
donating 10-formyltetrahydrofolate and can be inhibited the polymorphic enzyme thiopurine methyl transferase
by the antifolates methotrexate and pemetrexed. (TPMT) with S-adenosylmethionine serving as cofac-
tor. The methylated thiopurine bases cannot react with
CHEMISTRY The two currently marketed purine antican- HGPRT and, therefore, cannot form the active false ribo-
cer agents are both 6-thio analogs of the endogenous nucleotides. Drug manufacturers take this into account
purine bases guanine and purine, also known as inosine when establishing dosing regimens. The active false ribo-
(Fig. 37.32). They are prodrugs and must be converted nucleotide 6-thioinosinic acid is also subject to extensive
to ribonucleotides by hypoxanthine guanine phosphori- TPMT-catalyzed methylation. The S-methyl-6-thioinosinic
bosyl transferase (HGPRT) before they can exert their acid metabolite is a potent inhibitor of the amidophospho-
cytotoxic actions (Fig. 37.39). Mercaptopurine, acting ribosyl transferase enzyme and contributes to the cytotoxic
through a methylated ribonucleotide metabolite, inhib- action of the parent drug (Fig. 37.39). In contrast, little
its the target amidophosphoribosyl transferase enzyme, or no 6-methylthioguanylic acid is produced inside the cell
leading to the true antimetabolic effect of lowered AMP (130,131).

SH Ribose-5'-phosphate SH antimetabolic 6-methylthioinosinic acid, thus enhancing

N N N N sensitivity to the drug (131). In contrast, extensive TPMT
N N metabolizers show a decreased sensitivity to thioguanine
R N HGPRT R N
H because there is no compensatory increase in the forma-
H2O3PO H2C
O
Thiopurine tion of methylated ribonucleotide to offset the decreased
H
prodrug production of 6-thioguanylic acid (130).
HO OH Xanthine oxidase competes with TPMT for mercap-
6-Mercaptopurine
Active thiopurine ribonucleotide
(R = H) topurine (but not for thioguanine) and converts it to
6-Thioguanine 6-Thioinosinic acid (R = H) inactive 6-thiouric acid, which is excreted in the urine
(R = NH2) 6-Thioguanylic acid (R = NH2) (Fig. 37.40) (135). 6-Thioinosinic acid is also subject to
metabolism via the xanthine oxidase pathway, ultimately
TPMT TPMT
SAM SAM forming the same inactive metabolite. Allopurinol, which
inhibits xanthine oxidase and increases levels of active
6-thioinosinic acid, can be coadministered with mercap-
S-CH3 topurine to increase its duration of action and antineo-
S-CH3
N N plastic potency. The dose of mercaptopurine can be cut
N N
R N N approximately in half when coadministered with allopu-
R N N
H H2O3PO H2C
O
rinol. Coadministration of allopurinol with thioguanine
H
is not warranted, since the impact of xanthine oxidase on
S-Methyl-6-mercaptopurine HO OH
its metabolic degradation is minor.
(R = H)(inactive)
S-Methyl-6-thioguanine Active S-methythiopurine SPECIFIC DRUGS (FIG. 37.32)
(R = NH2)(inactive) ribonucleotide (R= H) Mercaptopurine Mercaptopurine is used in the treat-
FIGURE 37.39 Thiopurine metabolism leading to activation and ment of acute lymphatic and myelogenous leukemia. It
inactivation. is available in an oral dosage form, but absorption can be
erratic and is reduced by the presence of food. The drug
is extensively metabolized on first pass and excreted by
TPMT is polymorphic in humans, and some individuals the kidneys. Bone marrow suppression is the major use-
do not express this protein to any significant extent (132). limiting toxicity, although the drug can be hepatotoxic in
Patients who are poor TPMT metabolizers (e.g., 10% of high doses. Dosage adjustments should be considered in
Caucasians, but also evident in other races) will not experi- the face of renal or hepatic impairment. Since the major
ence the activity-attenuating metabolic effect and will gen- mechanism of action of mercaptopurine is inhibition
erate more active ribonucleotide per dose than patients of de novo purine nucleotide biosynthesis rather than
with normal or excessive levels of the enzyme. The TPMT apoptosis secondary to the incorporation of false nucleo-
genotype of patients should be assessed before initiating tides into DNA, there is a lower risk for mutagenesis and
thiopurine therapy because poor metabolizers are at a high secondary malignancy compared to thioguanine (130).
risk of life-threatening myelosuppression from elevated
levels of false ribonucleotides, even when standard doses
are administered (131). In addition, the accumulation of SH
SH N
mutagenic thiopurine-based ribonucleotides puts these N
N HGPRT
patients at higher risk for secondary malignancies (130). N
R N N
Thiopurines can still be used in poor TPMT metaboliz- N N H2O3PO H2C
O
H
ers, but the dose should be decreased significantly (e.g.,
H
10- to 15-fold) and white blood cell counts monitored vigi- Mercaptopurine
HO OH
lantly. Mercaptopurine appears to be more significantly
impacted by TPMT genotype than thioguanine (133). 6-Thioinosinic acid
(active)
Genes that encode for inositol triphosphate pyrophos- Xanthine
oxidase
phatase (ITPA) are also known to impact the metabolic Guanase
and toxicity profiles of mercaptopurines. Carriers of
the rs41329251 ITPA allele appear to be at significantly
SH SH
higher risk for the development of mercaptopurine- H
N Xanthine N N
induced febrile neutropenia even after TPMT genotype- N
O
oxidase
based dosage adjustment (132,134). HO N N
H
HO N N
H
Extensive TPMT metabolizers, who represent up to
90% of patients on thiopurine therapy, will form lower 6-Thiouric acid 6-Thioxanthine
(inactive) (inactive)
amounts of apoptotic 6-thiolated ribonucleotides. In
the case of mercaptopurine, the molecules of ribonu- FIGURE 37.40 Xanthine oxidase inactivation of mercaptopurine
cleotide generated will be methylated very rapidly to the and 6-thioinosinic acid.

Resistance to mercaptopurine (and thioguanine) ther- NH2 NH2
apy may have as much to do with attenuated active uptake N Deoxycytidine N

via nucleoside transporters as with the more commonly O N kinase O N
cited deficiency in the activating HGPRT enzyme (136). HO-CH2 O H2O3PO-CH2 O
HO HO
Thioguanine Thioguanine is administered orally in the
treatment of nonlymphocytic leukemias. Like mercapto- HO HO
purine, absorption is incomplete and variable, and the Cytarabine Ara-cytidine monophosphate
toxicity profiles are similar except where previously noted. (Cytidine arabinoside)
DNA Polymerase/DNA Chain Elongation Inhibitors Deoxycytidylate Pyrimidine mono-

Cytidine
MECHANISM OF ACTION Five halogenated and/or ribose- deaminase and diphosphate
deaminase
kinase
modified DNA nucleoside analogs are marketed for the
treatment of a wide variety of hematologic cancers and O NH2
solid tumors (Fig. 37.32). These agents have complex HN N
and multifaceted mechanisms. All include inhibition of O N O N
DNA polymerase and/or DNA chain elongation among RO-CH2 O H4O9P3O-CH2 O
their actions and all nucleosides must be converted to HO HO
triphosphate nucleotides before activity is realized.
HO HO
CHEMISTRY As nucleosides, the DNA polymerase inhibi- Uracil arabinoside (R = H) Ara-cytidine triphosphate
Uracil arabinotide (R = H2O3P) (active)
tors are actively taken up into cells via a selective nucle-
(inactive)
oside transporter protein, so tumors deficient in this
transporter system will be resistant to these anticancer FIGURE 37.41 Cytarabine metabolism.
agents. Once inside the cell, specific kinases conduct the
essential phosphorylation reactions. In active triphos-
phate form, they can be mistakenly incorporated into the metabolite on the potentially degradative deoxycytidine
growing DNA chain, thus arresting further elongation, monophosphate deaminase enzyme (110). Gemcitabine
and/or inhibit enzymes essential for DNA synthesis. All elimination is gender-dependent, with women having the
drugs in this group are administered intravenously, are greater risk for toxicity due to lower renal clearance.
excreted via the kidneys, and induce myelosuppression as Gemcitabine is indicated in the treatment of breast, pan-
their major use-limiting side effect. Resistance can involve creatic, and non-small cell lung cancers. Cytarabine, which
aberrations in the expression of metabolizing enzymes can be administered subcutaneously and intrathecally in
as well as of transporting and efflux proteins. Some in additison to intravenously, is used in the treatment of vari-
vitro evidence points to the loss of functional nucleoside ous leukemias. A liposomal formulation of cytarabine is
transporter proteins (specifically hENT1/SLC29A1) and available for the treatment of lymphomatous meningitis.
deoxycytidine kinase enzymes as the primary causes of
acquired resistance to DNA polymerase inhibitors (137). Fludarabine, Cladribine, and Clofarabine Like their pyrim-
As alluded to earlier, there is significant commonality idine counterparts, these 3-halogenated adenosine-based
in the enzymes involved in the activation and inactivation nucleosides undergo conversion to the active triphosphate
of these five antineoplastics, and the search is on for bio- nucleotides after active transport into tumor cells. All are
markers that can reliably predict the degree of sensitiv- initially phosphorylated by deoxycytidine kinase, and
ity to their therapeutic and potentially fatal toxic effects. cells with high levels of this enzyme should respond well
Several polymorphic genes are under active investigation to these agents. The C2-halogen renders the molecules
as candidates to assist practitioners in successfully indi- relatively resistant to the degradative action of adenosine
vidualizing antimetabolite chemotherapy (138). deaminase, and a significant fraction of the dose is elimi-
nated unchanged via the kidneys. Fludarabine, an arabi-
SPECIFIC DRUGS (FIG. 37.32) noside, is marketed as the monophosphate nucleotide to
Cytarabine and Gemcitabine Both of these cytidine- enhance water solubility for intravenous administration,
based anticancer agents undergo initial phosphoryla- but this group is cleaved rapidly in the bloodstream, allow-
tion by deoxycytidine kinase to the monophosphate with ing the free nucleoside to take advantage of the nucleo-
subsequent phosphorylations catalyzed by pyrimidine side-specific transporting proteins.
monophosphate and diphosphate kinases. Cytarabine, Cladribine is indicated in the treatment of hairy cell leu-
an arabinoside, is catabolized by cytidine and deoxy- kemia, whereas fludarabine phosphate is used in chronic
cytidylate (deoxycytidine monophosphate) deaminases lymphocytic leukemia. In addition to myelosuppression,
to inactive uracil analogs (Fig. 37.41). The significantly fludarabine phosphate can induce hemolytic anemia, and
longer half-life of gemcitabine (19 hours) compared to severe CNS toxicity has been noted with high doses.
conventional cytarabine (3.6 hours) is due to the inhibi- Clofarabine is used in acute lymphoblastic leukemia
tory action of the difluorodeoxycytidine triphosphate patients who are 21 years or less and who have failed with

at least two previous regimens. In addition to inhibiting severe central depression, and peripheral neuropathy
DNA chain elongation, this drug also inhibits ribonucleo- that can mimic Guillain-Barr syndrome. These adverse
tide reductase and facilitates the release of proapoptotic effects are considered dose-limiting. As noted earlier,
proteins from mitochondria. The rapid attenuation of leu- nelarabine can be metabolized to uric acid. Along with
kemia cells after administration of this agent can result in hydration and urine basification, the xanthine oxidase
a condition known as tumor lysis syndrome, and respira- inhibitor allopurinol can be given prophylactically to
tory and cardiac toxicities can occur secondary to cytokine minimize risk of nelarabine-induced hyperuricemia.
release. Toxicity can progress to potentially fatal capillary
leak syndrome and organ failure, and patients should Azacitidine and Decitabine Azacitidine and decitabine
receive intravenous fluids for the entire 5-day course of are given intravenously (and, in the case of azacitidine,
therapy to minimize risk of serious adverse events. subcutaneously) for the treatment of myelodysplastic syn-
drome. Patients should be monitored for hematologic
DNA Methyltransferase Inhibitors and renal toxicities while undergoing therapy with either
MECHANISM OF ACTION In contrast to the DNA alkylating agent, although renal toxicity is a more serious concern
agents discussed earlier in this chapter, three nucleic with azacitidine use. Both drugs are known to cause fetal
acidbased chemotherapeutic agents, azacitidine, harm, and patients should be actively counseled to take
decitabine, and nelarabine (Fig. 37.42), block abnormal appropriate reproductive precautions.
cellular proliferation by inhibiting DNA alkylation (spe-
cifically methylation) on genes responsible for differenti- MISCELLANEOUS ANTIMETABOLITES (FIG. 37.32)
ation and growth. The hypomethylation effect, mediated Pentostatin Pentostatin is a ring-expanded purine ribo-
through the inhibition of DNA methyltransferase, can nucleoside that inhibits adenosine deaminase and is pri-
sometimes restore normal gene function while selectively marily used in the treatment of hairy cell leukemia. The
killing cells that have stopped responding to the bodys elevated levels of deoxyadenosine triphosphate that result
cellular proliferation control processes. from inhibition of this degradative enzyme inhibit the
All of the marketed DNA methyltransferase inhibitors action of ribonucleotide reductase (the enzyme that con-
are nucleoside analogs that, once converted to triphos- verts ribose diphosphate to deoxyribose diphosphate),
phate nucleotides, are mistakenly incorporated into DNA thus halting DNA synthesis within the tumor cell. When
in lieu of their cytidine or guanine nucleotide counter- used in chronic lymphocytic leukemia, some authors
parts. Interaction of the false nucleotide with methyltrans- claim pentostatin offers a therapeutic efficacy compara-
ferase results in an irreversible inhibition of the enzyme. ble to fludarabine, but with a lower risk of toxicity (139).
CHEMISTRY All of these nucleoside analogs hydrolyze in Hydroxyurea Hydroxyurea, a drug with a 100-plus year
aqueous solution and must be administered soon after history, blocks the synthesis of DNA by trapping a tyrosyl
the dose is constituted. Their vulnerability to deami- free radical species at the catalytic site of ribonucleotide
nase enzymes explains their short elimination half-lives reductase, thereby inhibiting the enzyme that converts
of less than or equal to 4 hours. Nelarabine will also be ribonucleotide diphosphates into their corresponding
O-demethylated prior to DNA incorporation and can be deoxyribonucleotides. It is used orally for the treatment of
further metabolized to guanine, xanthine, and uric acid. melanoma, metastatic or inoperable ovarian cancer, resis-
Anemia, neutropenia, and thrombocytopenia are among tant chronic myelocytic leukemia, and as an adjunct to
the most common side effects of this class of drugs. radiation in the treatment of squamous cell carcinoma and
cancer of the head and neck. Hydroxyurea increases the
SPECIFIC DRUGS (FIG. 37.42) effectiveness of radiation therapy through its selective tox-
Nelarabine Nelarabine is considered third-line treat- icity to cells in the radiation-resistant S phase and by stall-
ment for T-cell acute lymphoblastic leukemia or lym- ing the cell cycle in the G1 stage, in which radiation therapy
phoma. The drug can induce severe and potentially does the greatest damage. It addition, hydroxyurea thwarts
irreversible neurologic symptoms including convulsions, the normal damage-repair mechanisms of surviving cells.
A review of its chemical, pharmacologic, metabolic, and
therapeutic properties has recently been published (140).
NH2 NH2 OCH3 Hydroxyurea has excellent oral bioavailability (80% to
N N N N N N 100%), and serum levels peak within 2 hours of consum-
N
ing the capsules. If a positive response is noted within 6
O N O N H2N N
HO-CH2 O HO-CH2 O HO CH2 O
weeks, toxicities are mostly mild enough to permit long-
OH
term or indefinite therapy on either a daily or every-3-day
basis. Leukopenia and, less commonly, thrombocytope-
HO OH HO OH nia and/or anemia are the most serious adverse effects.
Excretion of the unchanged drug and the urea metabo-
Azacitidine Decitabine Nelarabine lite is via the kidneys. The carbon dioxide produced as a
(Vidaza) (Dacogen) (Arranon)
by-product of hydroxyurea metabolism is excreted in the
FIGURE 37.42 DNA methyltransferase inhibitors. expired air.

Mitosis Inhibitors Polymerization involves the addition of tubulin dimers

The mitotic process depends on the structural and to either end of the tubule, although the faster-growing
functional viability of microtubules (polymeric het- (+) end is more commonly involved. Polymerization
erodimers consisting of isotypes of - and -tubulin results in tubular elongation, whereas depolymerization
proteins). These distinct but nearly identical 50-kd results in the shortening of the structure. The frenetic
proteins lie adjacent to one another within the tubule alteration in structure, facilitated by microtubule-asso-
and roll up to form an open, pipe-like cylinder akin to ciated proteins (MAPs), ultimately allows the formation
a hollow peppermint candy stick. A -tubulin protein of the mitotic spindle and the attachment to chromo-
is found at the organizational center of the microtu- somes that are prerequisites to cell division. Inhibiting
bule. The tubulin isotypes found in the microtubule the essential hyperdynamic changes in microtubular
are conserved throughout specific tissues within a given structure results in mitotic arrest and apoptosis. Two
species and will impact the cells sensitivity to mitosis general chemical classes of mitosis inhibitors have his-
inhibitors. torically been marketed for the treatment of cancer: tax-
During cell division, tubulin undergoes intense, spo- anes, and vinca alkaloids (141). They have been joined
radic, and alternating periods of structural growth and by the single agents estramustine, an estrogen-based
erosion known as dynamic instability. The proteins nitrogen mustardlike carbamate originally thought to
alternatively polymerize and depolymerize through act via DNA alkylation, and the epothilone ixabepilone
guanosine triphosphate- and Ca2+-dependent processes. (Fig. 37.43).
Taxanes
O
H3C C O H O H3C O
O H C O (CH3)3C O O H C O (CH3)3C O O H C O
3 3
10 9 OH 3
OH 10 OCH3
10
3' NH 3' NH 3' NH
7 O 7
1' O 13 6 O 13 7
1
HO 2' 2 4 H H HO H
O HO O O
HO O HO O HO O O
O O O O O
Ac Ac Ac
O O O
Paclitaxel (Taxol) Docetaxel (Taxotere) Cabazitaxel (Jevtana)
Epothilone Nitrogen mustard

2
O PO3
CH3
S O
H3C CH3 2 Na
N
H3C OH
Cl O
H
H3C CH3 N C O
HN Cl
CH3
O OH O
Ixabepilone (Ixempra) Estramustine phosphate sodium (Emcyt)
Catharanthine
Vinca alkaloids: portion
2 2
SO4 SO4
6' OH H OH H
H COO
N N N CH2CH3
CH2-CH3 CH OH
9'
2' 4' CH2-CH3
HO CH
N 18' 1' N N H CO2H
H H H 2
N N N
H3CO2C H3CO2C H3CO2C
CH2CH3 CH2CH3 H4 CH2CH3
H4 H4 3
3 3 H3CO N OAc
H3CO N OAc H3CO N OAc H
1 H H CO2CH3
CO2CH3 OH
C OH CO2CH3 H3C OH H3C
O H 2 2
Vindoline portion
Vincristine sulfate (Vincasar PFS) Vinblastine sulfate (Velban) Vinorelbine tartrate (Navelbine)
FIGURE 37.43 Mitosis inhibitors.

Taxanes taxane antineoplastics differ in substitution pattern at

MECHANISM OF ACTION Anticancer taxanes initially were iso- C13 (benzamido or t-butoxycarboxamido), C10 (second-
lated from the bark of the Pacific yew (Taxus brevifolia) but ary alcohol, acetate ester, or methoxy ether), and/or C7
are now produced semisynthetically from an inactive natu- (secondary alcohol or methoxy ether). The taxane ring
ral precursor (10-deactetylbaccatin III) found in the leaves system is often conceptualized as having northern and
of the European yew (Taxus baccata), a renewable resource. southern halves. The southern segment is critical to
Taxanes bind to polymerized (elongated) -tubulin at a receptor binding, whereas the northern section ensures
specific hydrophobic receptor site comprised of the 31 the proper conformation of essential functional groups,
N-terminal residues located deep within the tubular lumen including the C13-isoserine side chain [with its C1-carbonyl,
(142). At standard therapeutic doses (which should lead to free C2-(R)-OH and C3-(S)-benzamido or t-butoxycarbox-
intracellular concentrations of 1 to 20 M), taxane-tubulin amido groups], the benzoyl and acetyl esters at C2 and C4,
binding promotes a stable tubulin conformation similar to respectively, and the intact oxetane ring (145147).
that of the guanosine triphosphate-bound protein, which The key taxanetubulin binding interactions are
renders the microtubules resistant to depoly-merization identified in Table 37.8 using paclitaxel as ligand
and prone to polymerization (143). This promotes the (133,148,149). Paclitaxel interacts at the -tubulin bind-
elongation phase of microtubule dynamic instability at the ing site in a folded (T or butterfly) conformation that
expense of the shortening phase and inhibits the disas- places C2-benzoyl and the C3-benzamido groups in close
sembly of the tubule into the mitotic spindle. In turn, this proximity (145,149). Their independent intermolecular
interrupts the normal process of cell division. At these con- engagement with a critical -tubulin His residue per-
centrations, extensive polymerization causes the formation fectly positioned between them keeps them from inter-
of large and dense aberrant structures known as asters, acting with one another. The oxetane ring of taxanes,
which contain stabilized microtubule bundles. although capable of enhancing receptor affinity through
Taxanes are substrates for P-gp, and cellular efflux hydrogen bonding (146,148), is believed to serve a more
via this carrier protein is a major mechanism of taxane critical role in properly orienting the C4-acetyl moiety
resistance. It has also been demonstrated that patients for interaction within its hydrophobic binding pocket
who express a mutant variety of the oncogene p53 that (146). The C1-OH also promotes conformational stabil-
causes the overexpression of MAP4, and subsequently ity through intramolecular interaction with the carbonyl
promotes microtubular polymerization/elongation, oxygen of the C2 benzoyl moiety (145). The areas of the
show enhanced sensitivity to taxane chemotherapy and a paclitaxel structure where steric influences are most criti-
resistance to vinca alkaloids (144). cal to receptor binding have been identified (147).
CHEMISTRY Chemically, diterpenoid taxanes consist METABOLISM The taxanes are metabolized to signifi-
of a 15-membered tricyclic taxane ring system (tricy- cantly less cytotoxic metabolites by CYP450 enzymes
clo[9.3.1.0]pentadecane) fused to an oxetane (D) ring (Fig. 37.44). In humans, CYP2C8 bioconverts pacli-
and contain an esterified -phenylisoserine side chain taxel to 6-hydroxypaclitaxel, the major metabolite,
at C13. As shown in Figure 37.43, the three marketed which is 30-fold less active than the parent structure
TABLE 37.8 Paclitaxel-Tubulin Binding Interactions (142,145,146)

Paclitaxel Functional Group -Tubulin Binding Residues Interaction
C2-benzoyl phenyl Leu217, Leu219, His229, Leu230 Hydrophobic
C2-benzoyl carbonyl Arg278 Hydrogen bond
C3-benzamido NH Asp26 Hydrogen bond
C3-benzamido carbonyl His229 Hydrogen bond
C3-phenyl Ala233, Ser236, Phe272 Hydrophobic
C4-acetyl Leu217, Leu230, Phe272, Leu275 Hydrophobic
C7-OH Thr276 Ser277, Arg278 Hydrogen bond
C12-CH3 Leu217, Leu230, Phe272, Leu275 Hydrophobic
C3-OH Arg369, Gly370 (NH) Hydrogen bond
C3-carbonyl Gly370 (NH) Hydrogen bond
Oxetane oxygen Thr276 (NH) Hydrogen bond

2
HO O
HO
O H NH
HO
O 3'
2-Hydroxypaclitaxel HO
3'-Hydroxypaclitaxel O
HO
H3C C O
CYP3A4 O OH O H C O
3
CYP3A4 OH
OH CYP3A4 3' NH
6 O OH
6
CYP2C8 H H
Paclitaxel HO O
O HO O
O O O
Ac Ac
O
6-Hydroxypaclitaxel
(major metabolite)
3', 6-Dihydroxypaclitaxel
H2C OH
H3C O O
CH3
NH
CYP3A4
Docetaxel
3'
HO
Hydroxydocetaxel
HO
H3C O
OCH3
RO
H
C
HO
YP
O O
O
3A
Ac
4/
5
O
HO
O
/5
H3C
A4
10 OH
P3
CY
10-Desmethylcabazitaxel RO 7
(active) H
Cabazitaxel
HO O O
O
/5
CY
H3C O Ac
A4
P3
O
P3
H3C O
A4
CY
OH
/5
10
RO 7
H 7,10-Didesmethylcabazi-
HO
taxel (doxetaxel, active)
O O
O
Ac
O
7-Desmethylcabazitaxel
(active)
FIGURE 37.44 Metabolism of the taxane analogs.
(150153). CYP3A4 mediates the formation of addi- Hydroxydocetaxel is further oxidized and cyclized to iso-
tional minor p-hydroxylated metabolites of the benza- meric oxazolidinediones before excretion. Cabazitaxel is
mido and benzoyl moieties at C3 and C2 respectively, metabolized predominantly (80% to 90%) by CYP3A4/5,
and the 10-desacetyl metabolite has been documented with CYP2C8 taking on a minor biotransformation role.
in urine and plasma. Docetaxel is oxidized exclusively by Three active metabolites (including docetaxel) result
CYP3A4/5, with CYP3A4 having a 10-fold higher affin- from O-demethylation at C7 and/or C10. The elimination
ity for the drug than CYP3A5. The major metabolite, of taxanes is predominantly biliary.
known as hydroxydocetaxel, is the hydroxymethyl deriva- The metabolic patterns of these closely related struc-
tive of the 3-t-butoxycarboxamide side chain (153). tures are distinct, and it has been hypothesized that

the C13 side chain plays a major role in positioning the S O

CH3
compounds in the catalytic site of CYP450 enzymes. H3C CH3

N
Specifically, the 3-phenyl ring of paclitaxel has been pro- H3C OH
H
posed to properly orient C6 for hydroxylation through H3C CH3
O
-stacking interactions with CYP2C8 active site residues CH3
while decreasing affinity for CYP3A4 binding groups. The O OH O
hydrophobic character of the 10-acetoxy group, found in
Epothilone B
paclitaxel, enhances CYP450-mediated hydroxylation two-
to fivefold by facilitating substrate binding or augmenting CH3
S O
catalytic capability. Both isoforms are impacted by the H3C CH3
N
presence of this ester, often to the same extent (153). H3C OH
H
H3C CH3
Epothilones HN
CH3
CHEMISTRY Low water solubility is a significant drawback O OH O
to the therapeutic utility of the taxanes. This is particu-
Ixabepilone (Ixempra)
larly true of paclitaxel, which has a more lipophilic ace-
tate moiety at C10 compared to docetaxels more polar FIGURE 37.46 Epothilones.
hydroxyl group. Paclitaxel must be administered in a
vehicle of 50% alcohol/50% polyoxyethylated caster oil
(Cremophor EL), which can lead to an enhanced risk has a higher antineoplastic potency (149,155,156). The
of hypersensitivity reactions (dyspnea, hypotension, lactam analog ixabepilone has a comparable anticancer
angioedema, and urticaria) in patients not pretreated activity with an even higher water solubility and better in
with H1 and H2 antagonists and dexamethasone (154). vivo and in vitro stability (Fig. 37.46). The story of the dis-
As noted previously, high P-gpmediated cellular efflux covery and subsequent development of this lactam as the
of paclitaxel and docetaxel can result in drug resistance. lead compound in the search for a paclitaxel alternative
To overcome these problems, epothilones, 16-membered makes for interesting reading (157).
macrolides structurally unrelated to the taxanes but with Despite some conformational differences in ring sys-
functional groups properly positioned to mimic critical tem substituents between epothilones and taxanes, they
tubulin-binding groups, are being actively investigated are presumed to share a common or overlapping tubulin
for use in a variety of solid tumor and hematologic binding site, an assumption supported by the discovery
cancers (Fig. 37.45). Epothilone B, one of the original of tubulin mutants that are resistant to both classes of
structures investigated, binds with very high affinity to antimitotics (158). Comparing crystal structures of tubu-
the taxane binding site on polymerized -tubulin, and it lin-bound epothilone A (the 12-desmethyl derivative of
acts through the same cytotoxic mechanism. In addition epothilone B) and paclitaxel documents that the smaller
to enhanced water solubility and a lack of P-gp affinity, macrolide fills only about half the binding site volume
epothilone is more efficiently produced through fermen- of the larger taxane ligand. The binding site is plastic,
tation with the myxobacterium Sorangium cellulosum and and residues adjust their side-chain conformations to
accommodate either drug. Despite being surrounded
by identical tubulin residues, the only common binding
CH3 interaction involves a hydrogen bond between Arg282
Ixabepilone O
and the 7-OH group of taxanes or epothilones.
S CH3
H3C OH
H3C N
H CH3 SPECIFIC DRUGS (FIG. 37.43)
H3C
HN Paclitaxel Paclitaxel, which is claimed to be the best-
CH3 selling anticancer drug in history (145), is indicated for
O OH O
intravenous use in combination with cisplatin as first-line
therapy for advanced ovarian and non-small cell lung can-
R2 O
cer. It is also used alone or in combination with the fluo-
O rouracil prodrug capecitabine in anthracycline-resistant
HO O H3C OH
metastatic breast cancer. Paxclitaxels ability to upregulate
O thymidine phosphorylase, one of capecitabines activating
NH
O enzymes, is the rationale behind the combination ther-
HO O
O O apy (159). Solution (Taxol, Onxol) and albumin-bound
Paclitaxel Ac
O (Abraxane) formulations are available and cannot be used
interchangeably. Abraxane, which does not require the
hypersensitivity-inducing Cremophor EL in its formulation,
FIGURE 37.45 Complementary ixabepilone and paclitaxel has also been used in various solid tumors of the GI and
functional groups. genitourinary tracts. Solution-based infusions usually are

administered over 3 to 24 hours and can be passed through retention commonly observed with docetaxel, but periph-
an in-line, 0.22-m filter to reduce vehicle-related cloudi- eral motor and/or sensory neuropathy can be persistent.
ness. The albumin-bound form is given over 30 minutes Its relatively high incidence of diarrhea (50%) may be
and should be well mixed (but not filtered) to ensure com- explained by the accumulation of the drug in entero-
plete suspension of the protein-drug particles. A paclitaxel cytes, cells that constitutively express P-gp and, therefore,
receptor targeting peptide conjugate designed for selective actively evict other taxanes. Despite the conversion of the
drug delivery to the CNS is in clinical trials (142). two secondary alcohols to more lipophilic ethers, caba-
Besides hypersensitivity reactions common with zitaxels aqueous solubility is on a par with docetaxels.
the nonalbumin-bound formulations, the major use- Like docetaxel, it is formulated with polysorbate 80 rather
limiting adverse effect of paclitaxel is dose-dependent than the more hypersensitivity-inducing Cremophor EL,
myelosuppression, particularly neutropenia, and first although antihistamine/corticosteroid pretreatment is
doses might need to be decreased in patients with hepatic still recommended (160). It is administered by intrave-
dysfunction. Subsequent dose reductions, if any, should nous infusion in doses of 25 mg/m2 every 3 weeks.
be tailored to individual response. The drug should not
be given to patients who have baseline neutrophil counts Ixabepilone The epothilone ixabepilone is used in
below 1,500 cells/mm3. The albumin-bound formula- combination with the thymidylate synthesis inhibitor
tion is also associated with sensory neuropathy. As noted capecitabine in anthracycline- and/or taxane-resistant
earlier, all patients receiving solution-based paclitaxel advanced or metastatic breast cancer, or when these alter-
should be pretreated with antihistamines and a cortico- native drugs are contraindicated. Some phase II clinical
steroid to minimize the risk of potentially fatal hypersen- trials have shown overall response rates to this agent
sitivity reactions. Paclitaxel is a Category D teratogen and as high as 57% in previously untreated breast cancer
carries a high risk of fetal intrauterine mortality. Both patients and up to 30% in patients who had been heavily
male and female patients are advised not to attempt pretreated (164). As noted previously, the lactam moiety
conception while on this drug. Due caution should be provides stability to in vivo hydrolysis by carboxylester-
observed when coadministering paclitaxel with drugs ases, but the drug is extensively metabolized by CYP3A4
that inhibit or compete for metabolizing enzymes, partic- to over 30 inactive metabolites prior to predominately
ularly CYP2C8 (e.g., 17-ethinylestradiol and diazepam). fecal excretion. Drugdrug interactions with CYP3A4
substrates, inducers, or inhibitors have been reported,
Docetaxel The indications for docetaxel as a rule mirror and dosage adjustments may be warranted if coadminis-
those of paclitaxel, although docetaxel is not used in ovar- tration cannot be avoided. Like cabazitaxel, ixabepilones
ian cancer. It has greater water solubility than paclitaxel due serious use-limiting adverse reactions include peripheral
to presence of the free C10-OH group, and it is formulated neuropathy (67%) and neutropenia. Like paclitaxel, it
with polysorbate 80 rather than with polyoxyethylated cas- requires Cremophor EL for solubilization, so hypersen-
tor oil. Hypersensitivity reactions, while less likely, are still sitivity reactions are likely, and prophylactic premedica-
possible, and all patients should receive corticosteroid pre- tion is required. The most common intravenous dosage
medication. In addition to neutropenia and teratogenicity, regimen is 40 mg/m2 administered over 3 hours every
this taxane can induce significant fluid retention, and 2-kg third week.
weight gains are not uncommon. Although rare, onycholy-
sis has also been reported. Drugdrug interactions have Vinca Alkaloids
been noted when docetaxel is coadministered with drugs MECHANISM OF ACTION Several alkaloids found naturally in
that inhibit or compete for CYP3A4 enzymes (e.g., azole Catharanthus roseus (periwinkle) have potent antimitotic
antifungals, erythromycin, and cyclosporine) (160). activity. In opposition to the taxoids, vinca alkaloids halt
cell division by inhibiting polymerization. They bind at
Cabazitaxel Cabazitaxel is the 7,10-dimethoxy analog the interface of two heterodimers within the inner tubu-
of docetaxel. Conversion of the two secondary alcohol lar lumen at a single high-affinity site on -tubulin in
groups to methoxy ethers dramatically lowers affinity for the vicinity of the guanosine triphosphate binding site
P-gp, resulting in sustained retention in tumor cells along on the (+) end of the tubules. Once bound, these alka-
with a higher bloodbrain barrier penetration (161). loids attenuate the uptake of the guanosine triphosphate
Cabazitaxel has shown efficacy in docetaxel-resistant cell essential to tubule elongation (165). Simultaneous bind-
lines where resistance was due to P-gp overexpression. ing to - and -tubulin results in protein cross-linking,
Although currently approved for use only in docetaxel- which promotes a stabilized protofilament structure
resistant metastatic prostate cancer, cabazitaxel has shown (166). Inhibition of microtubule elongation occurs at
activity against a wide variety of human tumors including substoichiometric concentrations, at which alkaloid
colon, lung, pancreas, squamous cell, head and neck, occupation of only 1% to 2% of the total number of
and metastatic breast cancers (161163). Neutropenia is high-affinity sites can result in up to a 50% inhibition of
the most problematic dose-limiting reaction, although its microtubule assembly (167,168). At high concentrations,
incidence and severity are no worse than observed with when alkaloid binding to high-affinity sites becomes stoi-
other taxanes. Cabazitaxel does not promote the fluid chiometric and lower-affinity binding sites on the tubule

wall are also occupied, microtubular depolymerization lack of neurotoxicity permits its coadministration with
is stimulated, leading to the exposure of additional alka- cisplatin. It is known that acetylation of either hydroxyl
loidal binding sites and resulting in dramatic changes group destroys antineoplastic activity and reduction of
in microtubular conformation. Spiral aggregates, proto- the vindoline olefinic linkage greatly attenuates antineo-
filaments, and highly structured crystals form, and the plastic action (154). The C18-methoxycarbonyl and the
mitotic spindle ultimately disintegrates (143,159). The stereochemistry at positions 18 and 2 are also believed
loss of the directing mitotic spindle promotes chromo- to be critical to activity (169).
some clumping in unnatural shapes (balls and stars), Vinca alkaloids undergo O4-deacetylation to yield
leading to cell death (154). Other nonmitotic toxicities metabolites equal to or more active than the parent drug.
related to the microtubule-disrupting action of the vinca They are also subject to extensive CYP3A4/5-mediated
alkaloids include inhibition of axonal transport and metabolism before biliary excretion, although the
secretory processes and disturbances in platelet struc- structures of these metabolites are currently unknown
ture and function (167). (170173).
As noted earlier, the mutant p53 oncogene is associ-
ated with resistance to vinca alkaloidinduced cytotoxicity SPECIFIC DRUGS (FIG. 37.43)
due to its augmentation of MAP4-mediated microtubulin Vincristine Sulfate It has been estimated that over half
polymerization, which counteracts the depolymerizing of U.S. children with cancer who receive chemotherapy
mechanism of the alkaloids. In addition, the mutant will be given vincristine, as will more than 300,000 adult
oncogene gives a degree of immortality to stathmin, a cancer patients per year (170). The drug is given by the
cytosolic protein that must be inactivated for mitosis to intravenous bolus or continuous infusion routes in the
begin. Finally, p53 upregulates the MRP-1 efflux protein treatment of acute leukemia and various Hodgkins lym-
that ejects vinca alkaloids from cells. It has been sug- phomas and NHLs. Toxicity is often more pronounced
gested that p53 phenotype could be harnessed to better by the latter route.
predict a patients anticipated susceptibility to various Elimination of vincristine is triphasic, with the first
mitosis inhibitor antineoplastic therapy options (144). phase (5 minutes) representing rapid uptake into tis-
sues and the last phase (85 hours) representing release
CHEMISTRY The specific chemical nature of the vinca back to the plasma from tubulin-containing cells. Since
binding site remains elusive due to difficulties encoun- the drug is extensively metabolized by O4-deacetylation
tered in binding assay development and implementation, and CYP3A5-catalyzed oxidation in the liver, patients with
as well as in data analysis. It is known that the active site is hepatic dysfunction are at an increased risk for toxicity,
close to residue 339 and residue 390 on - and -tubulin, and dosage reductions should be considered. The most
respectively (168). Of the three marketed vinca alkaloids significant dose-limiting adverse effect is peripheral neu-
(vincristine, vinblastine, and vinorelbine), vincristine ropathy, which is initially manifested as numbness and
binds most tightly, whereas vinblastine has the low- painful paresthesias in the extremities and progresses to
est affinity (167). Because vinca alkaloids enter cells by muscular pain, severe weakness, and loss of coordination.
simple passive diffusion, unbound vinorelbine and vin- Patients can also experience constipation secondary to
blastine (being more lipophilic than vincristine) may be intestinal neurotoxicity, which may require treatment
more extensively taken up into tissues. Vincristine, how- with cathartics. African American patients, who com-
ever, is cleared more slowly from the system and has the monly carry the CYP3A5*1 allele that expresses a catalyti-
longest terminal half-life of the three agents, resulting in cally active CYP3A5 enzyme, are at lower risk for severe
a more prolonged tumor cell exposure (143,167). Like and/or prolonged neurotoxicity than Caucasians, who
the taxanes, tumor resistance to vinca alkaloids is medi- carry less active/inactive alleles (170). Myelosuppression
ated, in part, through P-gp. is not particularly problematic because it occurs at doses
The vinca alkaloids are complex structures composed higher than those that can be tolerated. As previously
of two polycyclic segments known as catharanthine (or noted, coadministration with mitomycin can induce
velbanamine) and vindoline (Fig. 37.43), both of which acute or delayed pulmonary toxicity characterized by
are essential for high-affinity tubulin binding. The three severe bronchospasm.
commercially available anticancer alkaloids differ in the All vinca alkaloids are severe vesicants that can induce
length of the alkyl chain bridging positions 6 and 9 of necrosis, cellulitis, and/or thrombophlebitis. Proper
the catharanthine moiety (methylene or ethylene), in needle placement before administration should be
the substituents at position 4 (olefin or tertiary alcohol), assured to eliminate the risk of extravasation. Unlike the
and in the N1 vindoline indole nitrogen (methyl or for- tissue damage caused by the vesicant action of nitrogen
myl). Although subtle, these structural changes lead to mustards and antibiotic antineoplastics, cold exacerbates
significant differences in clinical spectrum, potency, and tissue destruction. If extravasation occurs, apply heat for
toxicity. For example, vincristines relative lack of bone 1 hour 4 times a day for 3 to 5 days, coupled with local
marrow toxicity at standard therapeutic doses makes it hyaluronidase injections. Vinca alkaloids are all Category
popular in combination therapy with more myelosup- D teratogens and are fatal if administered by the intrathe-
pressive anticancer agents, whereas vinblastines relative cal route.

Vinblastine Sulfate In addition to the hematologic OH
indications that it shares with vincristine, vinblastine Hydrolysis

has found utility in the treatment of advanced testicu- Estramustine
phosphate sodium
lar carcinoma (often in combination with bleomycin), Cl
N C O
advanced mycosis fungoides, Kaposi sarcoma, and Cl O
Hydrolysis
histiocytosis X. Leukopenia is the dose-limiting side
effect, and dose reductions are warranted in patients OH
Estradiol-3-bis(chloroethyl)carbamate
with serum bilirubin levels greater than 3 mg/dL. The
drug-related impact on erythrocyte and thrombocyte
levels is usually insignificant. Like vincristine, it is
administered as an intravenous bolus or infusion. The HO
initial elimination half-life of 3.7 minutes is similar to DNA cross-linking by intact mustard
Estradiol (minor therapeutic impact)
vincristine, but the 24.8-hour terminal half-life is sig-
nificantly shorter. FIGURE 37.47 Estramustine metabolism.
Vinorelbine Tartrate Vinorelbine is used alone or in

combination with cisplatin for first-line treatment of active 17-OH. The 3-carbamate group is also cleaved in
non-small cell lung cancer. This semisynthetic alkaloid is vivo to generate estradiol (Fig. 37.47), which explains
unique in having oral bioavailability (167), but it is cur- why this drug is not used to treat estrogen-dependent
rently available only for intravenous injection. The initial tumors (e.g., estrogen-dependent breast cancer). The
phase elimination half-life is on a par with that observed liberated estradiol may also increase blood pressure and
for vincristine and vinblastine, and the terminal phase induce blood clots, leading to myocardial infarction.
half-life is between 28 and 44 hours. Although dose- Fortunately, the myocardial infarctions are usually non-
limiting granulocytopenia is the major adverse effect, fatal, but the drug should be used with extreme caution
potentially fatal interstitial pulmonary changes have in men who are predisposed to clotting disorders or who
been noted. Patients with symptoms of respiratory dis- have a history of cerebral vascular disease or coronary
tress should be promptly evaluated. Biotransformations artery disease. Hepatotoxicity is also associated with
include deacetylation and N-oxidation. As with all vinca estramustine use.
alkaloids, elimination is primarily hepatobiliary, and dos-
age reduction should be considered in patients with liver Tyrosine Kinase and Related Inhibitors
dysfunction. Aberrations in the activity of protein tyrosine kinases
(TKs) are associated with several neoplastic disorders,
Estramustine Phosphate Sodium Because this antican- and it has been estimated that more that 80% of human
cer agent contains a carbamylated nitrogen mustard oncogenes and proto-oncogenes direct the expression of
moiety, it was originally thought to function as a DNA these essential phosphorylating enzymes. When function-
alkylator; however, it is now known that its primary ing normally, TKs regulate cell proliferation, differen-
mechanism of antineoplastic action is inhibition of tiation, and survival. When functioning in a deregulated
mitosis. Estramustine binds to MAP-4, prompting disso- manner, they accelerate cell signaling cascades and cel-
ciation of this protein from the microtubule and promot- lular growth, induce tumors, augment antiapoptotic
ing depolymerization and disassembly. It can also bind processes, and, in so doing, confer resistance to many
directly to - and -tubulin at a site distinct from the chemotherapeutic drugs.
vinca alkaloid and taxane binding sites, although pacli-
taxel exerts a noncompetitive inhibition of estramustine MECHANISM OF ACTION TKs are of two general types, recep-
binding to tubulin. A specific estramustine binding pro- tor-associated and cellular (nonreceptor), both of which
tein in prostate tissue is believed to facilitate its action are ATP-dependent. The highly conserved ATP binding
in the treatment of metastatic carcinoma of the prostate. domain of the TKs serves as the receptor for antineoplas-
Estramustine has a low affinity for the m tubulin isotype, tic TK inhibitors (TKIs, or tyrphostins). This hydropho-
which is often overexpressed in estramustine-resistant bic domain, a depression or groove rich in isoleucine
prostatic neoplasms as one defense against this therapeu- (Ile), leucine (Leu), alanine (Ala), and valine (Val) resi-
tic intervention (159,174). dues, is found in the hinge region that connects the
Estramustines resonance-stabilized, mustard-like amino terminal (N) and carboxy terminal (C) lobes of
-haloalkylamine carbamate structure uses an estradiol the catalytic unit. A minimum of five potential binding
carrier to selectively deliver drug to steroid-dependent pockets surround this site, which may help explain the
prostate tissue, and its use is limited to the palliative otherwise surprising degree of selectivity exhibited by
treatment of progressive prostate cancer. The ionized many anticancer TKIs (175). Van der Waals, hydropho-
sodium phosphate ester makes the compound water sol- bic, hydrogen-bonding, and electrostatic interactions are
uble and able to distribute in the blood. The phosphate all of prime importance in holding ATP and the TKIs to
ester is readily cleaved during absorption to provide the this enzymatic domain (175,176).

TKs that serve as targets for anticancer TKIs include TKIs inhibit several kinase enzymes and are referred to as
EGFR, VEGFR, human epidermal growth factor recep- multikinase inhibitors.
tor 2 (HER2), platelet-derived growth factor receptor CYP3A4 is a common TKI-metabolizing isoform, and
(PDGFR), Bcr-Abl (a product of the translocated break- many TKIs inhibit a variety of cytochrome P450 (CYP)
point cluster [BCR]-Abelson [ABL] gene known as the enzymes. Several TKIs are also substrates for, and inhibi-
Philadelphia, or Ph, chromosome), and Src. Bcr-Abl tors of, cellular efflux pumps like P-gp and breast cancer
and Src are nonreceptor kinases, whereas the remain- resistance protein (BCRP). All are excreted predomi-
ing are receptor-associated enzymes. Type 1 inhibitors nantly in the feces. The structures of the currently mar-
bind to the active conformation of the kinase, whereas keted TKIs are shown in Figure 37.48.
type 2 TKIs inhibit the enzyme in its inactive conforma-
tion. Since the inactive conformation of TKs differs in Bcr-Abl Inhibitors: Imatinib, Nilotinib, and Dasatinib
structure to a greater degree than the active conformer, CHEMISTRY Bcr-Abl inhibitors were the first TKIs to be
it has been proposed that type 2 inhibitors may have a introduced, and they literally changed the face of CML
better opportunity for selectivity (175,177). Promiscuous therapy. The aberrant Ph chromosome is viewed as the
Bcr-Abl kinase inhibitors:
H CH3
N H CH3
CH3 CH3 N O
H H H
N N N N H3C N N S
N N NH
Cl
N N N N Cl CH3
CH3SO3
HN C N
O N CF3
H
N O N
N
OH
Imatinib mesylate Nilotinib hydrochloride Dasatinib
(Gleevec) (Tasigna) (Sprycel)
EGFR kinase inhibitors:
H
O N H3CO N
CH3O
Cl
CH3O N N
O N O
HN C CH O HN Cl
F
Erlotinib hydrochloride Gefitinib
(Tarceva) (Iressa)
EGFR and HER2 kinase inhibitor:

N
O N
N HO3S CH3
H HN Cl
O S O 2
CH3 F
O
Lapatinib ditosylate
(Tykerb)
VEGFR kinase inhibitors:
O H
CH3 C2H5 O CF3
H H3C N H3C
N N N N SO2NH2 N C2H5 N O Cl
H H O
H3C N HCl
N F N CH3 O N
CH3 H H N N
CH3 O H H
O O3S
N
H HO CO2H
Pazopanib hydrochloride Sunitinib malate Sorafenib tosylate
(Votrient) (Sutent) (Nexavar)
CH3
FIGURE 37.48 Tyrosine kinase inhibitors.

single cause of more than 90% of adult CML. The clini- Asp381
Glu286
cal availability of imatinib, discovered serendipitously
in a search for new anti-inflammatory agents, allowed
Thr315
patients to realistically anticipate a 5-year survival, as Leu285 H3C
CH3
opposed to the 2- to 3-year prognosis for patients with Val289 H
O
N
untreated disease. The drug has its greatest effect in the H N N N C
N
initial (chronic) phase of CML and is significantly less H N
effective in the accelerated or highly fatal blastic phases. CF3 N

As is the case with so many chemotherapeutic agents, Leu298 Phe359
acquired resistance has undermined the positive clinical Val299 Met318
outcomes this drug first promised. Resistance mecha- Nilotinib
nisms are often associated with point mutations in the
Abl (kinase) domain, in particular a threonine (Thr) Thr315
Leu284
to Ile mutation at position 315 (T315I). Residue 315 is Gly321 Ile313
known as the gatekeeper to the hydrophobic binding H3C
H O
pocket, and the more significant bulk of the Ile residue N S
C N
Met290
blocks imatinibs access to this receptor through steric H
N Ala380
N N N Cl
interference with the benzyl moiety (175,178). Alternate HO
N Val299
mechanisms of resistance are related to BRC-ABL gene CH3 Met318
amplification, P-gp overexpression, underexpression of
an organic cation transporter-1 protein that helps ima- Thr320
tinib (but not nilotinib) gain access to cells, and activa- Dasatinib
tion of Src kinases. Although nilotinib can show activity FIGURE 37.49 Binding interactions between tyrosine kinase and
in some imatinib-resistant mutants, it cannot overcome selected Bcr-Abl inhibitors.
the resistance induced by T315I. Twelve percent of all
Bcr-Abl mutations are T315I, and CML patients carrying
this mutation have a poor prognosis. rings, respectively. The lower pKa of imidazole compared
The Bcr-Abl inhibitors imatinib and nilotinib contain to piperazine explains why nilotinib is not a substrate
a 2-phenylaminopyrimidine pharmacophore. They are for the organic cation transporter-1 protein that ferries
relatively large, extended structures that bind to both the imatinib into cells and contributes to imatinib resistance
ATP hinge region and to adjacent hydrophobic subdo- (182).
mains of the Bcr-Abl protein. As type 2 inhibitors, they The trifluoromethyl moiety of nilotinib engages in
bind to the inactive conformation of the kinase known unique affinity-enhancing hydrophobic interactions with
as the DFG-out state (177). In this conformation, an Leu298, Val299, and Phe359, which are, in part, responsible
enzymatic aspartate (Asp175) (D)-Mg+2 interaction is bro- for nilotinibs 30- to 50-fold increase in TK-inhibiting
ken, and a Phe residue is pushed out toward the aque- potency compared to imatinib. The methylimidazole
ous environment, occluding the approach of ATP and moiety also augments affinity through hydrophobic
generating a new binding area that attracts type 2 Bcr- interactions with Leu285, Glu286, and Val289, while leaving
Abl inhibitors. This conformation is also stabilized by an the basic nitrogen exposed to the aqueous environment
unphosphorylated Tyr393, which orients toward the cen- (175,177179).
ter of the enzyme and H-bonds with Asp363 (179). In contrast to imatinib and nilotinib, dasatinib is a
The o-methyl substituent found on imatinib and nilo- mixed type 1 and type 2 Bcr-Abl kinase inhibitor that also
tinib confers selectivity for the cytosolic Bcr-Abl protein has significant affinity for cellular Src kinases. Although
in its inactive conformation, although the benzamide it contains a pyrimidine ring, this moiety does not bind
moiety permits some inhibition of PDGFR kinase. It is in the hinge region as the pyrimidine rings of imatinib
the PDGFR-related component of the activity profile that and nilotinib do. Rather, this binding honor goes to
is believed responsible for the fluid retention induced aminothiazole, and it is facilitated by a critical hydro-
by these two TKIs. These agents also contain a pyridyl gen bond between the thiazole nitrogen and the amide
substituent at C4 of the pyrimidine ring, which enhances NH of Met318. Met318s carbonyl oxygen also binds to the
affinity through H-bonding with the amide NH of Met318 hydrogen of the amino group connecting the thiazole
within the hinge region of the kinase (Fig. 37.49). The and pyrimidine rings. A third hydrogen bond between
amide moiety, inverted in nilotinib compared to ima- the drugs amide nitrogen and the hydroxyl of gate-
tinib, forms H-bonds with Glu286 and Asp381 (180,181). keeper residue Thr315 ensures high affinity for the active
Yet another H-bond is formed between gatekeeper (DFG-in) state of the kinase (178).
Thr315 and the NH group connecting the pyrimidine The 2-chloro-6-methylbenzamide segment of dasatinib
and phenyl rings. Water solubility and the favorable binds deep within the hydrophobic pocket of the kinase
oral bioavailability profiles of imatinib and nilotinib are in an area distinct from the ATP-binding site. Interactions
conferred by the substituted piperazine and imidazole between this aromatic moiety and Thr315, Met290, Val299,

Ile313, and Ala380 are known (183). Hydrophobic interac- with back pocket residues of the active (open) enzyme.
tions with Leu248 and Gly321 also hold the pyrimidine ring The H-bonds formed between the quinazoline nitrogen
to the kinase. As in imatinib, dasatinibs water solubility is atoms and hinge residues Met793 (N1) and Thr790 (N3) are
assured through the hydroxyethyl-substituted piperazine crucial to activity. The halogenated and acetylene-sub-
ring, which is oriented toward the hinge region and is stituted phenyl rings of gefitinib and erlotinib, respec-
solvent-exposed. An H-bond between this moiety and the tively, are maintained at a 42-degree angle relative to the
backbone carbonyl oxygen of Thr320 is known to occur. quinazoline ring and, in this orientation, bind well in
Dasatinibs ability to bind to the active kinase confor- the hydrophobic pocket near Thr790 as long as this gate-
mation has been attributed to the fact that it does not keeper residue remains small (175). A T790M mutation
insert into the hydrophobic pocket containing Phe(F)382, is believed responsible for acquired resistance to these
as the substituted benzyl moiety of imatinib does (175). highly selective TKIs (186,187). Unlike the acquired Bcr-
Because it can bind to both the active and inactive con- Abl kinase resistance, which was steric in nature, an unfa-
formations of Bcr-Abl kinase, dasatinib has a potency vorable TKI/ATP binding affinity ratio in the T790M
approximately 325 times that of imatinib, and it can be mutant has been proposed to explain acquired resistance
used in patients resistant to imatinib or nilotinib. Most to EGFR TKIs (175).
mutations that confer resistance to imatinib occur in the Increasing the size of the 4 substituent with groups
P-loop of the kinase, an area not important to dasatinib like m-fluorobenzyloxy (lapatinib) restricts access to only
binding (183). Dasatinib is effective against all imatinib- the inactive conformation of EGFR (175) and broadens
resistant mutants except T315I, retains activity in cells TK specificity to include HER2. The entire substituted
made resistant to imatinib via activation of Src kinases, aniline structural component of lapatinib binds within
and does not bind to P-gp. a lipophilic pocket of the HER2 kinase in its inactive
(closed) conformation. The quinazoline ring of EGFR/
HER2 inhibitors again affiliates with residues in the
EGFR and EGFR/HER2 Inhibitors: Erlotinib, Gefitinib,
hinge region of the ATP-binding domain. Selectivity for
and Lapatinib
the inactive conformation of its target kinases (which
CHEMISTRY EGFR and HER2 are closely related mem- requires a conformational change to dislodge the inhibi-
brane-bound TKs. EGFR expression in solid tumors of tor) may contribute to the very slow (300 minutes)
the breast, lung, bladder, esophagus, and oral cavity has enzyme dissociation half-life compared to erlotinib and
been clearly correlated with decreased life expectancy gefitinib (30 minutes) (175).
(184), and it is a consistent presence in almost all epi- Lapatinibs 2-furanyl substituent can be further sub-
thelial-derived cancers. Likewise, HER2 overexpression stituted at position 5 with long, unbranched chains that
is a classic feature of treatment-resistant breast, ovar- extend out into the aqueous environment. The addi-
ian, lung, and gastric cancers, and it endows tumors tion of a methylsulfone moiety to the chain terminus
with whats been called an antiapoptotic shield (185). enhances water solubility. The ionizable morpholine ring
A unique Cys residue is located within the ATP-binding of gefitinib serves a similar purpose. The water solubility
domain, and TKIs capable of irreversibly inactivating the of erlotinib is predictably low given the relative lack of
protein through covalent bond formation with Cys797 polar functional groups in this area of the molecule.
(e.g., neratinib) are now being investigated (175,176).
VEGFR Inhibitors: Sunitinib, Sorafenib, and Pazopanib
O N
CHEMISTRY VEGF2 is a key enzymatic player in the gen-
H3C N C N C N eration of new blood vessels. Inhibition of this important
H
CH3 O HN TK starves tumors by inhibiting angiogenesis and keep-
ing oxygen and essential nutrients from supporting their
O CH2
Cl N continued uncontrolled growth. This deprivation, cou-
pled with the buildup of cellular waste materials, kills cells
Neratinib (Irreversible tyrosine kinase inhibitor) treated with TKIs that target this kinase. Augmenting the
cytotoxic effect is the fact that VEGF inhibition decreases
The currently marketed reversible EGFR TKIs all the permeability of tumor cell vasculature and eases
contain a 4-anilinoquinazoline pharmacophore with an intracellular delivery of chemotherapeutic agents (188).
oxygen-containing substituent at C6. Ether-containing The binding of sorafenib to VEGFR in its inactive
moieties of varying size are also permitted at C7. An elec- conformation is believed to be similar to its interaction
tron-withdrawing substituent at position 3 of the aniline with its originally recognized kinase target B-RAF, a com-
phenyl ring provides high selectivity for EGFR kinase as ponent of the RAS signal transduction network (175).
long as the 4 position remains unsubstituted (erlotinib) Assuming so, the pyridine nitrogen in its un-ionized
or is modified with a very small substituent such as fluo- form and the nearby methylamide NH moiety H-bond
rine (gefitinib). Erlotinib and gefitinib are quintessen- with the amide group of Cys919 in the hinge region (NH
tial type 1 TKIs, with the m-substituted phenyl ring of and carbonyl oxygen, respectively). The trifluoromethyl-
the aniline moiety enhancing affinity through binding phenyl moiety binds in a hydrophobic pocket, possibly

occupying the site normally reserved for Phe1047 in diarrhea, nausea, and rash. Myocardial toxicity and hepa-
the DFG-in (active) conformation, and the urea moi- totoxicity, while potentially severe, are rare.
ety forms H-bonds with several residues, including the
Asp1046 of the DFG trio. H
N
Unlike sorafenib, a type 2 TKI, sunitinib can inhibit H
CH3
VEGFR in both its active and inactive conformations. N N
N
The indolinone (or oxindole) moiety of sunitinib has N
been shown to confer high affinity for a hydrophobic HN
pocket within the ATP-binding domain of kinases (189).
N O
However, the selectivity of VEGFR TKIs is low, since
this kinase domain is replicated in many closely related Imatinib desmethyl metabolite
enzymes, such as PDGFR and c-kit, that are associated (active)
with GI stromal tumors (GISTs) (190). Broad activity
against several kinases is expected, particularly from Nilotinib Hydrochloride Nilotinib is indicated in newly
inhibitors that are retained exclusively within this con- diagnosed or imatinib-resistant Ph+ CML. It is supplied
served nucleotide-binding region and that avoid neigh- as 150- and 200-mg capsules, and twice-daily doses of
boring residues that permit differentiation of kinase 300 mg (new diagnosis) and 400 mg (resistant disease)
affinity profiles (e.g., sunitinib). Sorafenibs pyridine are standard. The oral bioavailability of nilotinib is much
ring interacts with amino acids in the kinase ATP-binding lower than imatinib (30% vs. 98%, respectively). Taking
domain, whereas the urea component of the bisarylurea the drug within 30 minutes of a high-fat meal increases
moiety augments affinity through H-bonding. oral bioavailability to 50% and the area under the curve
Geometric isomerism is important to the TKI activ- by 82% (193), and this can result in an increased risk of
ity of sunitinib, with the lower energy Z isomer being serious toxicity. No food should be eaten 2 hours before
over 100 times as potent as the higher energy E isomer. or 1 hour after administration. Biotransformation is lim-
Exposure to light will prompt a Z to E isomeric inversion, ited, with the major metabolite being a carboxylic acid
with a return to the lower energy Z state over time in the arising from CYP3A4-mediated hydroxylation of an aro-
dark (191). matic methyl group. No metabolites are active. Sixty-nine
Sunitinib and sorafenib enter cells via passive diffu- percent of a dose is excreted unchanged (191).
sion as opposed to carrier-mediated transport (192). All
currently marketed VEGFR TKIs are used in the treat- O
C OH
ment of renal cell carcinoma (RCC), a highly vascular- CH3 N
ized tumor (177). H
N N
N
N
SPECIFIC DRUGS (FIG. 37.48)
Imatinib Mesylate Imatinib is indicated in Ph+ CML, O N CF3
H
acute lymphoblastic leukemia, GIST (a tumor expressing N
a c-kit kinase mutation), and myeloproliferative diseases.
Nilotinib oxidized metabolite
Available in 100- and 400-mg tablets, recommended (inactive)
doses in patients with adequate renal function run mostly
between 400 and 600 mg daily. The drug should be taken
Nilotinib is associated with life-threatening toxicities,
with a large glass of water and with food to minimize GI
including QT interval prolongation that can progress to
distress.
torsades de pointes, sudden death, and myelosuppres-
Imatinib has a 98% mean oral bioavailability, and max-
sion. The risk of potentially fatal myocardial toxicity is
imum serum concentrations are achieved within 4 hours.
elevated if the drug is taken with food or coadministered
It is metabolized predominantly by CYP3A4-mediated
with potent CYP3A4 inhibitors. Nilotinib doses should
N-dealkylation to an equally active desmethyl metabolite
be cut in half if CYP3A4 inhibitors must be coadminis-
(191). Serum levels of imatinib will increase if coadminis-
tered and reduced in patients with hepatic impairment.
tered with CYP3A4 inhibitors, and the drug should not be
Patients should also be counseled to avoid grapefruit
given with grapefruit juice. Conversely, the dose of ima-
juice and St. Johns wort.
tinib should be increased by 50% if coadministration with
potent CYP3A4 inducers (e.g., cyclosporine) is warranted.
Imatinib is a competitive inhibitor of CYP3A4, CYP2C9, Dasatinib Dasatinib is available as 20-, 50-, 70-, and 100-
and CYP2D6, and care should be taken when substrates mg tablets for use in Ph+ CML and acute lymphoblastic
of these isozymes are coadministered. The parent drug leukemia patients who are resistant or intolerant to other
and active desmethyl metabolite have elimination half- therapies, including imatinib. The starting dose is 140 mg
lives of 18 and 40 hours, respectively. Approximately 25% once daily, and patients should be titrated up or down to
of a dose is excreted as the unchanged drug. Although the maximum dose tolerated. Doses higher than 180 mg
well tolerated, common adverse effects include edema, daily are not recommended. Oral bioavailability is low due

to poor absorption and rapid first-pass CYP3A4-mediated 100 to 150 mg daily are common, and the product is mar-
metabolism. Biotransformations include aromatic keted as 25-, 100-, and 150-mg tablets. Because adminis-
hydroxylation, benzylic hydroxylation, N-dealkylation, tration with food significantly increases oral absorption
N-oxidation (at piperazine N4), and oxidation of the from 60% to 100%, patients are instructed to take the
hydroxyethyl moiety (Fig. 37.50). drug 1 hour before or 2 hours after eating to minimize
FMO-3 and uridine diphosphate glucuronyl transfer- toxicity risks.
ase also catalyze minor metabolic reactions (193). All five Extensive CYP3A4-mediated O-dealkylation of the ter-
CYP3A4-generated metabolites retain activity, but repre- minal methoxy group of the C6 side chain occurs, and
sent only 5% of the parent area under the curve, so their some molecules of the primary alcohol are further oxi-
clinical relevance is questionable. The p-hydroxylated dized by cytosolic enzymes to the carboxylic acid. CYP1A1
metabolite can be oxidized to a potentially hepatotoxic and CYP1A2 can also catalyze this reaction, and erlo-
quinoneimine (191). The mean elimination half-life of tinibs half-life and area under the curve are dramatically
dasatinib is 3 to 5 hours, and 19% of a dose is excreted decreased in cigarette smokers (191). Coadministration
unchanged (191). Doses should be decreased (20 to of strong CYP3A4 inducers has the same effect.
40 mg daily) or increased (as tolerated) if CYP3A4 inhibi- Conversely, erlotinib doses must be decreased in 50-mg
tors or inducers, respectively, must be coadministered. increments if serious side effects occur with coadminis-
Like other drugs in this class, dasatinib also inhibits tration of CYP3A4 inhibitors. The potentially fatal hepa-
CYP3A4, and it should not be taken with grapefruit juice. totoxicity that can be induced by this drug might be due,
Dasatinib can be taken with or without food, and at least in part, to the formation of an electrophilic qui-
myelosuppression, peripheral edema, and GI distress are noneimine from a CYP3A4- and CYP1A1-generated phe-
the most commonly encountered adverse effects. Unlike nolic metabolite (Fig. 37.51) (191).
nilotinib, there is no black box warning related to pro- In addition to hepatotoxicity, erlotinib can cause
longation of the QT interval, but the potential of dasat- diarrhea and a maculopapular skin rash that has been
inib to exacerbate the toxicity of agents that do should positively correlated with therapeutic efficacy. The rash
not be ruled out. worsens when exposed to sunlight, so patients should be
counseled to take appropriate precautions. Erlotinib is
Erlotinib Hydrochloride Erlotinib is used in the treat- both a substrate and an inhibitor of P-gp and, like other
ment of non-small cell lung cancer in patients whose TKIs, it inhibits CYP isoforms, specifically CYP3A4 and
disease has either stabilized after four rounds of organo- CYP3A5.
platinum therapy or progressed after completion of a
nonTKI-based chemotherapeutic regimen. It is also Getinib Gefitinib is used exclusively as a single agent
used in combination with gemcitabine as first-line ther- in the treatment of organoplatinum- and docetaxel-
apy in advanced or metastatic pancreatic cancer. Doses of refractory non-small cell lung cancer. One 250-mg tablet
O
NH OH HO
N
Cl CH2 CH3O
O
N Alcohol dehydrogenase
OH Aldehyde dehydrogenase
O CYP3A4 CYP3A4/1A1/1A2
CYP3A4 (oxidation) (O-dealkylation)
(benzylic hydroxylation)
O
H
H3C N N S O
NH
O N O
N N Cl CH3 CH3O HO
N CYP3A4 CH3O N CH3O
N O O
(N-oxidation) HN C CH
N
N Dasatinib
O OH
OH Erlotinib
CYP3A4 (aromatic hydroxylation)
CYP3A4
(dealkylation)
CYP3A4/1A1
(aromatic hydroxylation)
N
NH N
Cl CH3 Cl CH3
N
H N C CH
H N C CH
OH O O
OH
Hepatoxic Hepatotoxic
quinoneimine quinoneimine
FIGURE 37.50 Dasatinib metabolism. FIGURE 37.51 Erlotinib metabolism.

is administered daily without regard to meals. Higher ($2,500 to $3,000 per month), and the fact that the area
doses induce more toxicity without additional therapeu- under the curve can be increased threefold by taking the
tic benefit. drug with a high-fat meal has caused some to question
CYP2D6, along with CYP3A4/3A5, catalyzes the deal- whether this pharmacokinetic profile could be safely
kylation of the quinazoline 7-methoxy ether to a pheno- harnessed to lower costs without compromising clinical
lic metabolite with equal in vitro EGFR-inhibiting action outcomes (191).
but limited therapeutic relevance due to polarity-induced CYP3A4 is the major lapatinib-metabolizing enzyme
difficulties in tumor cell penetration (193). Enzymatic and catalyzes the oxidative removal of the m-fluoroben-
cleavage and subsequent loss of the morpholine ring zyl moiety. Doses are decreased to 500 mg daily when
occur to a lesser extent, as do defluorination and subse- potent CYP3A4 inhibitors are coadministered, and
quent p-hydroxylation of the aniline phenyl moiety. As titrated up to a maximum of 4,500 to 5,500 mg daily (as
noted with other TKIs, oxidation of the p-phenol to a tolerated) when exposure to potent CYP3A4 inducers is
reactive quinoneimine may occur in both liver (CYP3A4) required.
and lung (CYP1A1) (Fig. 37.52). Smokers can generate
N
up to 12 times more of this reactive metabolite than non-
smokers (191). O N
N
Like erlotinib, gefitinib induces rash (a consequence O S O
H HN Cl
of its EGFR kinase specificity) and diarrhea. Between CH3
40% and 50% of patients on the 250-mg daily dose will OH
experience these two side effects. Infrequent but serious Lapatinib dealkylated metabolite
toxicities include potentially fatal interstitial lung disease
(possibly related to quinoneimine formation), interstitial Severe diarrhea is the most common dose-limiting
pneumonia, worsening pulmonary fibrosis, and corneal adverse reaction, but potentially fatal hepatotoxicity
ulceration. The drug induces aberrant eyelash growth, was the prompt for a black box toxicity warning for this
which can induce eye pain. agent. Given that the o-chlorinated phenolic metabolite
generated by CYP3A4 could generate a quinoneimine as
Lapatinib Ditosylate This dual kinase inhibitor is used electrophilic and hepatotoxic as the one formed from
in combination with capecitabine as second-line therapy gefitinib (Fig. 37.52), along with the high (1,250 mg)
in the treatment of HER2-positive advanced or metastatic daily dose, the warning is not surprising. Other serious
breast cancer. Patients receiving this drug should have side effects are cardiovascular in nature and include
previously received anthracycline, taxane, and trastu- decreased left ventricular ejection fraction and arrhyth-
zumab therapy. Five 250-mg tablets are administered mia. The characteristic EGFR kinase-related rash is expe-
daily on an empty stomach. The drug is very expensive rienced by approximately 28% of patients taking this
drug. Lapatinibs 24-hour half-life is along the lines of
other TKIs. Like other drugs in this class, lapatinib inhib-
its CYP isoforms (CYP3A4 and CYP2C8), P-gp, and BCRP
HO N
O
H3CO N efflux proteins.
N N
O HO O Sunitinib Malate Sunitinib is indicated in the treat-
ment of advanced RCC and imatinib-resistant kit-
CYP2D6 (dealkylation) positive GIST. Its introduction in 2006 more than
doubled the rate of positive therapeutic outcomes
Multiple
steps previously achieved with interferon- or interleukin-2
H3CO N in RCC patients (40% vs. 2% to 20% response rates)
N (191). The drug is supplied as 12.5-, 25-, and 50-mg cap-
N O
O HN Cl
sules and is administered daily on a 4 weeks on/2 weeks
off regimen. Patients are usually started on 50 mg and
Gefitinib F then titrated up or down in 12.5-mg increments until
an acceptable balance of benefit-to-toxicity is achieved.
Absorption is independent of food, but could possibly
Defluorination/hydroxylation
be impacted by body mass index, which could partially
explain the wide individual variability in bioavailability
H
N Cl
N Cl (193).
CYP3A4 deethylates sunitinib to an equally active
O
OH secondary amine metabolite whose serum levels are
Hepatotoxic approximately one-third of the parent drug (191). All
quinoneimine
precautions outlined for other CYP3A4-vulnerable kinase
FIGURE 37.52 Gefitinib metabolism. inhibitors should be taken.

O
C2H5 once daily on an empty stomach. Nonlinear kinetics are
H3C N
N observed when doses exceed this maximum. The drug
H
CH3
H is a substrate for CYP3A4 and P-gp, and it has a half-life
F N
O
H of approximately 31 hours. Drug-induced hepatotoxicity
N can be severe, and patients with moderate hepatic dys-
H
function should not take more than 200 mg daily. Serious
Sunitinib dealkylated metabolite cardiovascular and GI toxicities have also been noted.
(active)
mTOR Inhibitors
Like many TKIs, sunitinib is a substrate for P-gp. MECHANISM OF ACTION Mammalian target of rapamycin
The terminal half-life of sunitinib and its N-deethylated (mTOR) is a serine/threonine kinase that is regulated
metabolite can extend up to 60 and 100 hours, respec- through the action of phosphatidylinositol (175). When
tively. The highly conjugated structure imparts a yellow activated, it phosphorylates kinases that ultimately result
color to the drug and its metabolites, which can be trans- in the de novo synthesis of proteins (including VEGF)
ferred to skin and body fluids. Patients often experience that promote growth. The kinase domain of this 289-kd
diarrhea, hand-foot syndrome (a consequence of drug protein is in the C-terminal area, with the 100-residue
leakage from palmar and plantar capillaries), and fatigue. macrolide-binding domain (known as FKBP12-FRB)
More serious treatment-associated adverse events include located just to its N-terminal side. The two marketed
potentially fatal hepatotoxicity, left ventricular dysfunc- mTOR inhibitors are O13 analogs of rapamycin, a bacte-
tion and arrhythmias, and elevated blood pressure. It has rium isolated from soil (Fig. 37.53).
been estimated that almost one-fifth of patients on this
drug discontinue it, with women and the elderly being at HO
highest risk for adverse events (191). O
O HO
H3C
Sorafenib Tosylate This TKI is indicated for the treatment O OCH3
of advanced RCC and unresectable hepatocellular carci- CH3
noma. For either indication, the dosing regimen is one O

200-mg tablet twice daily on an empty stomach. Nonlinear O
kinetics manifest when doses of more than 400 mg/day are O
N O OCH3
administered. Important to its use in hepatocellular carci-
noma, doses are cut in half in patients with moderate hepatic O O
impairment, and patients with severe hepatic impairment H
cannot usually take this drug. Interestingly, when hepatic Rapamycin

dysfunction progresses to the very severe stage, 200-mg
maximum daily doses are again tolerated (191). Slow tablet CHEMISTRY Rapamycin binds tightly to FKBP12 and FBR
disintegration in the GI tract and enterohepatic circulation and, by burrowing into the domain gap between these
may contribute to interpatient variability in serum concen- proteins, promotes an interaction that is not observed
trations, and about half of an administered dose of drug in the absence of the macrolide. This inhibits the abil-
will be lost to direct fecal elimination. ity of the kinase to function, albeit in a manner not yet
Between 9% and 16% of a dose of sorafenib is bio- understood. Van der Waals interactions with a number of
transformed by CYP3A4-mediated N-oxidation to an Tyr, Phe, and tryptophan (Trp) residues in the FKBP12
equally active metabolite, which subsequently undergoes
glucuronic acid conjugation. Side effects are similar to
those induced by sunitinib. Sorafenib is known to inhibit HO
a number of CYP isoforms including CYP3A4, CYP2D6, O
OH
CYP2B6, CYP2C19, and CYP2C8, but there appear to be
O OH O
no clinically significant interactions with substrates or
modifiers of these enzymes (193,194). OCH3 OCH3
O CF3
H3C O Cl O O OH O O OH
N O N N
H
N O O O O O O
N N O CH3O O CH3O
O H H HO HO
O OCH3 O OCH3
H H
Sorafenib N-oxide metabolite
(active)
Temsirolimus (Torisel) Everolimus (Afinitor)

Pazopanib Hydrochloride Like others in its class, pazo-
panib is indicated in RCC and administered at 800 mg FIGURE 37.53 mTOR inhibitors.

domain along with H-bonds with Asp and Tyr side chains histone proteins involved in regulating gene transcrip-
promotes high-affinity binding between inhibitor and tion. Exposure to these inhibitors is associated with an
enzyme. Hydrophobic interactions between the carbon- increase in the antioncogene p21, induction of cell cycle
rich macrolide and the kinase are known to occur and arrest, and subsequent apoptosis (195). The fact that a
are the only interactions believed to form with the FBR wide variety of proteins can undergo acetylation helps
domain (175). Rapamycin is 92% buried when bound to explain the significant impact of this therapy on cellular
these two mTOR domains, and only O13 (the site of modi- homeostasis (196). These agents are currently used intra-
fication in the commercially available rapamycin-based venously in the treatment of cutaneous T-cell lymphoma.
inhibitors), C40, and C41 (of the cyclohexane ring) contact
the surrounding environment. The polar nature of the O13 SPECIFIC DRUGS (FIG. 37.54)
ester and alcoholic substituents of temsirolimus and evero- Romidepsin Romidepsin is a depsipeptide histone
limus would promote solubility in these aqueous fluids. deacetylase inhibitor that induces a caspase-dependent
apoptosis and retains efficacy in cells overexpressing
SPECIFIC DRUGS (FIG. 37.53) the prosurvival protein Bcl-2 (197). It is a substrate for
Temsirolimus Temsirolimus is given as a 25-mg intra- CYP3A4 and P-gp. Side effects are, as a rule, manageable,
venous infusion once weekly to patients with advanced with fatigue, fever, and sepsis being the most commonly
RCC. Patients receiving this agent should be pretreated observed adverse reactions.
with 25 to 50 mg of diphenhydramine (or a related anti- Myelosuppression and GI distress are rare. The
histamine) 30 minutes prior to administration of the mac- belief that this agent induces QT interval prolongation
rolide to minimize the risk of hypersensitivity reactions. has recently been challenged, although serum electro-
In patients still responding positively after 6 months of lytes, particularly potassium and magnesium, should be
therapy, the drug should be continued for an additional brought within normal range before instituting therapy
6 months or for 2 months after complete remission, with this agent (198).
whichever occurs first. CYP3A4-mediated metabolism to
rapamycin (an active metabolite) demands avoidance of Vorinostat This hydroxamic acid histone deacetylase
inducers or inhibitors of this isoform if at all possible. If inhibitor has an overlapping mechanism with romidepsin,
coadministration of these agents is essential, appropriate but is not vulnerable to P-gpmediated efflux and loses
dosage adjustments should be made. it caspase-dependent apoptotic action in cells that over-
As an immunosuppressive agent, temsirolimus express Bcl-2 (197). It is inactivated by direct glucuronic
increases the risk of infection and delays wound healing. acid conjugation and/or hydrolysis at the hydroxamic
It also elevates blood glucose, cholesterol, and triglycer- acid end of the molecule and subsequent -oxidation
ide levels. Potentially fatal adverse events associated with to 4-anilino-4-oxobutanoic acid (199). Side effects are
temsirolimus include interstitial lung disease, bowel per- classified as GI, constitutional (e.g., chills, fever), hema-
foration, renal failure, and cerebral hemorrhage. tologic (thrombocytopenia, anemia), and taste-related.
Pulmonary embolism is also a risk of vorinostat therapy.
Everolimus Everolimus is an orally active rapamycin
analog that is supplied as 0.25-, 0.5-, 0.75-, 5-, and 10-mg H
N COOH
tablets. Ten-milligram doses are administered once daily
O
in the treatment of advanced RCC resistant to sunitinib
or sorafenib, whereas the lower doses (<1 mg) are used 4-Anilino-4-oxobutanoic acid
to stop rejection of transplanted kidneys. In patients with
moderate hepatic dysfunction, the antineoplastic dose is Vorinostat is available only to patients who are enrolled
cut to 5 mg once daily. in a manufacturer-sponsored program entitled Accessing
Unlike temsirolimus, therapy can continue for as long Coverage Today. Patients must specify their pharmacy so
as positive therapeutic outcomes are being achieved.
However, like temsirolimus, CYP3A4-mediated metabolism
requires appropriate dosage adjustments if strong induc- O O
ers or inhibitors of this isoform must be coadministered.
O
Major biotransformations involve monohydroxylation, H H
S
O-dealkylation, and cleavage of the large lactone ring. None NH N C (CH2)6 C N OH
S O HN H
of these metabolites are active. Everolimus shares many of O O
the same adverse effects as temsirolimus (immunosuppres- NH
O
sion, blood glucose elevation, and dyslipidemias) and can
also induce angioedema and ulceration of the oral cavity. NH
O
Histone Deacetylase Inhibitors
Romidepsin (Istodax) Vorinostat (Zolinza)
MECHANISM OF ACTION Several structural prototypes can
inhibit the deacetylation of Lys residues of the highly basic FIGURE 37.54 Histone deacetylase inhibitors.

that the medication can be provided for distribution by Phthalimide Glutarimide

O
those specific pharmacists. Pharmacists dispensing this H
drug to approved patients do not require special certifi- N *
cation or program enrollment (200).
OO N O
H
Immunomodulators CYP2C19 Thalidomide CYP2C19
SPECIFIC DRUGS (FIG. 37.55)
Thalidomide Anyone of the baby boomer or World O
O
War II generation will recognize the name of the drug H
H OH
N
thalidomide because it induced perhaps the most well- N
known incident of drug-associated birth defects in recent HO
OO N O
OO N O
H
history (201). Used in the late 1950s and early 1960s as H
an antiemetic and sedative in pregnant women, more 5'-Hydroythalidomide
5-Hydroxythalidomide
than 10,000 European children were born with flipper- (S-isomer) (R-isomer)
like arms and legs, a condition called phocomelia or seal
limb. Approximately half of those afflicted survived. CYP2C19/2C9/1A2
Although it is known that the teratogenic and sedative
actions of chiral thalidomide are mediated by different O
H
stereoisomers (202), the in vivo conversion of the thera- N
peutic R-isomer to its cytotoxic S-enantiomer prohibited HO
the use of this drug in women who were or could become OH OO N O
H
pregnant. Although not licensed in the United States
during these early years, the drug was banned by the U.S. 5,6-Dihydroxythalidomide
Food and Drug Administration (FDA) until 1997 (203).
FIGURE 37.56 CYP2C19-mediated thalidomide metabolism.
Despite this troubled beginning, the therapeutic
potential of thalidomide, when used wisely and ration-
ally, is significant (204). Its action as a tumor necrosis
factor inhibitor prompted the lifting of the FDA ban have been identified (Fig. 37.56). However, the extent of
to allow its use in the treatment of leprosy. Its antiprolif- formation shows significant individual variability, and the
erative and proapoptotic actions have now allowed it to clinical significance of this potential metabolic pathway
be approved for use in combination with dexamethasone in vivo is highly questionable.
in multiple myeloma (205,206). In addition to arresting Thalidomide can only be dispensed by pharmacists
uncontrolled cell growth, thalidomide denies multiple or other qualified providers who are registered with
myeloma cells access to bone marrow stromal cells and the System for Thalidomide Education and Prescribing
various growth factors needed for tumor cell survival and Safety (STEPS) distribution program (209), and women
augments circulating levels of natural killer cells, inter- of childbearing age may be given this drug only if no via-
leukin-2, and interferon- (202). The benefit of adding ble alternative exists, and then only with ongoing weekly
thalidomide to other chemotherapeutic regimens for (first therapeutic month) and monthly (thereafter)
multiple myeloma, and in treating other neoplastic dis- proof of nonpregnant status. Because the drug also finds
orders, is under active investigation (207). its way into semen, male thalidomide patients capable of
Thalidomide is marketed as 50-, 100-, and 200-mg cap- having sexual relations must agree to safety-promoting
sules. If tolerated, a 200-mg dose is administered at least restrictions on reproductive activities. Use-limiting
1 hour after the evening meal, preferably at bedtime. It adverse effects include peripheral neuropathy that can
undergoes spontaneous hydrolysis of the phthalimide be irreversible (most commonly with chronic use) and
and glutarimide moieties to generate 12 distinct thromboembolic events (e.g., deep vein thrombosis, pul-
hydrolysis products prior to renal elimination (208). monary emboli). The latter side effect is exacerbated by
Thalidomide has a minor vulnerability to stereoselective the coadministered dexamethasone. Other potentially
CYP2C19-catalyzed metabolism, and three metabolites problematic, but less serious, side effects include seda-
tion, fatigue, and constipation (202).
O NH2 Lenalidomide Lenalidomide has a similar activity pro-

H H file to its predecessor immunomodulator, thalidomide,
N N but is effective at a little more than one-tenth of the dose
OO N O OO N O (25 mg daily as opposed to 200 mg). The side effect pro-
H H file is milder, although because the drug is also coadmin-
istered with dexamethasone, significant thromboembolic
Thalidomide (Thalomid) Lenalidomide (Revlimid)
events can still occur. Neutropenia and thrombocytope-
FIGURE 37.55 Thalidomide-based immunomodulators. nia can also be dose-limiting. The potential for serious

dose-independent teratogenicity is the basis for restricted torsades de pointes, and complete atrioventricular block
use in people of reproductive potential. Practitioners dis- demands an assessment of serum electrolytes (particu-
pensing lenalidomide must be registered with RevAssist, larly magnesium and potassium) prior to the initiation
a distribution program similar to STEPS (210). of therapy. APL differentiation syndrome (also known
Despite having retained the glutarimide moiety that as retinoic acid syndrome and characterized by pleural/
was a prime target for nonenzymatic hydrolysis in tha- pericardial/pulmonary infiltrates or effusions, dyspnea,
lidomide, approximately two-thirds of a dose of lenalido- weight gain, and fatigue) responds to corticosteroid
mide is excreted unchanged in the urine. The drug is not intervention. Reversible hepatotoxicity has also been
a substrate for or an inhibitor or inducer of CYP enzymes noted, and the strong emetogenic potential of As2O3 war-
(211). rants coadministration of drugs to control nausea and
vomiting.
Miscellaneous Anticancer Agents Bortezomib (Proteasome Inhibitor) Facilitated by ubiq-
SPECIFIC DRUGS uitin tagging, proteasomes selectively clear cells of cyto-
Arsenic Trioxide (Proapoptotic) As noted at the start of plasmic regulatory proteins by cleaving them into short
this chapter, the toxic effects of arsenic have been recog- peptides. Inhibition of this homeostatic process induces
nized for millennia (212). Arsenic trioxide (As2O3, known apoptosis, at least in part through the dysregulation of
commercially as Trisenox) was originally introduced into unfolded protein response gene expression (214) and
Western medicine in the late 19th century for the treat- the inhibition of the activation of antiapoptotic factor
ment of leukemia and then fell out of favor as newer nuclear factor-B by proteasome substrate IB (215).
chemotherapeutic and radiation-based approaches to Bortezomib binds to the 20S proteasome (or core
care became available. The drug experienced a pharma- particle) component of the 26S proteasome, a highly
cotherapeutic renaissance in the late 20th century, and conserved protein that can cleave proteins essentially
it is currently used intravenously to induce remission in anywhere along the chain (216). The binding selectiv-
patients with acute promyelocytic leukemia (APL). APL is ity is quite high, as the estimated affinity ratio for this
characterized by the reciprocal translocation of chromo- proteasome and the next most attractive target protein
somes 15 and 17, resulting in the abnormal joining of the is over 1,500 (215). The crystal structure of the bort-
promyelocytic gene and retinoic acid receptor (213). ezomib-20S proteasome complex from yeast has been
This, in turn, results in the generation of immature leu- reported, and specific drugproteasome interactions
kemia cells, differentiation arrest, and the induction of have been identified (217). The multiplicity of potential
serious/fatal hemorrhagic and other coagulation-related binding sites encompassing multiple 20S subunits con-
disorders. Arsenic trioxide induces remission in APL firms the complex nature of its activity and may pave the
patients through the destruction of the offending fusion way for the development of more selective inhibitors with
protein, promotion of promyelocyte differentiation, and higher affinities and more desirable pharmacokinetic
stimulation of apoptosis in malignant cells. One docu- properties.
mented chemical apoptotic mechanism is inhibition of
intracellular catalase and glutathione peroxidase, with HO
B
OH
N O
the resultant accumulation of the free radical precursor H
N N
H2O2. Another is the downregulation of the antiapop- N
H
O
totic protein Bcl-2 (212). Arsenic trioxides indication
specifies use after therapy with an anthracycline and a
retinoid (e.g., tretinoin, trans-retinoic acid) has failed,
but there is evidence to show its efficacy as first-line ther- Bortezomib (Velcade)
apy in newly diagnosed or previously untreated patients
(213). Although patient numbers were relatively small,
Bortezomib is used intravenously in the treatment
complete remission rates ranging between 73% and 92%
of multiple myeloma and mantle cell lymphoma. The
have been reported.
boronic acid moiety is essential, as CYP-mediated debo-
O ronation yields a metabolite that does not inhibit the 26S
C proteasome. The drug is hydroxylated at various posi-
OH
tions prior to excretion, and the CYP isoforms involved
in the biotransformations include CYP3A4, CYP2C19,
trans-Retinoic acid and CYP1A2. Like many other anticancer agents, the
(Tretinoin) drug suppresses bone marrow, leading to neutropenia
and thrombocytopenia, and can induce serious sensory
The pentavalent As(V) in the parent drug is reduced (and less commonly motor) peripheral neuropathy.
to the active trivalent As(III) by arsenate reductase. Prior Neuropathy can often be managed with dose reduction,
to excretion, As(III) is methylated to mono- and dimeth- although drug discontinuation is required with grade
ylarsonic acid. Although arsenic trioxide is usually well 4 dysfunction (215). Cardiac and pulmonary complica-
tolerated, the possibility of QT interval prolongation, tions have also been reported.

OTHER CHEMOTHERAPEUTIC APPROACHES with either a cytotoxic calicheamicin-based antibiotic

or - and/or -emitting radioisotopes, are also commer-
Hormone Therapy cially available for the treatment of various neoplasms
Glucocorticoids (e.g., prednisone and methylpredniso- (Table 37.9) (218). The two murine MoAbs on the mar-
lone) are commonly administered with anticancer agents ket (ibritumomab tiuxetan and tositumomab) have a
to suppress lymphocytic activity and to enhance the chance momab ending in their names (mouse), as opposed to
of success in the treatment of leukemias and lymphomas. the humanized antibodies, which most commonly end
In addition, some tumors, such as estrogen-dependent in umab (human). Whether future marketed anticancer
breast cancer, endometrial cancer, and metastatic cancer MoAbs will support this helpful hint to antibody origin
of the prostate, depend on the presence of sex hormones remains to be seen.
for viability. In these neoplastic diseases, the use of steroid MoAbs target tumor cell antigens, and in unconju-
receptor antagonists, synthesis inhibitors, or gonadotro- gated form, the complex recruits endogenous immuno-
pin secretion inhibitors, either alone or in combination modulator and cell-destroying cytokines (e.g., natural
with other antineoplastic drugs, is a common approach to killer cells, macrophages) to stop the advancement of
chemotherapeutic care. Antiestrogens (e.g., tamoxifen), the cancer. The protein components of conjugated
antiandrogens (e.g., flutamide), progestins (e.g., meges- MoAbs are homing devices designed to selectively deliver
trol acetate), aromatase nhibitors (e.g., exemestane), and cell-killing chemicals attached to the antibody to tumor
luteinizing hormone-releasing hormone agonists (e.g., cells. It should be noted that some endogenous immuno-
leuprolide acetate) are all available for use in managing modulator/biologic response modifying proteins (e.g.,
hormone-dependent tumors and are often employed after interleukin-2) are also available as drug products to treat
surgery, radiation therapy, and/or other chemotherapy. selected solid and hematologic cancers.
The selected targeting of tumor cells over healthy cells
Enzyme Therapy (which do not express the target antigen to the extent
Exogenous asparagine (Asn) is essential to the survival malignant cells do) should promote a higher margin of
of malignant lymphocytic leukemia cells, because these safety for MoAbs when compared to administering toxins
cells lack asparagine synthetase enzymes. l-Asparaginase that can distribute as widely as their chemical properties
(also known as l-asparagine amidohydrolase) or its deriv- allow. The engineering of humanized or chimeric MoAbs
atives can be added to the chemotherapeutic regimen of has significantly attenuated the risk of therapy-sabotaging
patients with leukemia to deplete serum Asn by hydrolysis immunologic responses to the murine-derived proteins
to aspartate and ammonia. Being deprived of this avenue found in the early agents. However, black box warn-
for Asn acquisition, tumor cells die from an inability to ings for all MoAb anticancer agents except one (ofatu-
synthesize essential proteins. Normal cells, which contain mumab) caution against such potentially fatal events as
asparagine synthetase, are able to synthesize this essential infusion/hypersensitivity reactions, cytopenias, hemor-
nutrient and can withstand therapy. rhage, hepatotoxicity, infection, tumor lysis syndrome,
cardiomyopathy, and cardiopulmonary arrest.
Monoclonal Antibodies The interested reader is directed to several reviews on
Seven human, humanized, or chimeric monoclonal the clinical use of anticancer MoAbs that have recently
antibodies (MoAbs), as well as three MoAbs conjugated appeared in the literature (219222).
TABLE 37.9 Anticancer MoAbs (217)

MoAb Drug/Nuclide Cellular Cancer
Conjugate? Target
Alemtuzumab No CD52 B-cell CLL
Bevacizumab No VEGF Colorectal, lung
Cetuximab No EGFR Colorectal, head and neck
Gemtuzumab ozogamicin Calicheamicin CD33 Acute myeloid leukemia

90
Ibritumomab tiuxetan (murine) Y (-emitting isotope) CD20 NHL
Ofatumumab No CD20 CLL
Panitumumab No EGFR Colorectal
Rituximab No CD20 NHL
Tositumomab (murine) 131

I (- and -emitting isotope) CD20 NHL
Trastuzumab No HER2 Breast

SCENARIO: OUTCOME AND ANALYSIS

Outcome isoforms of cyclooxygenase that are responsible for the produc-
Kelly Nystrom, PharmD, BCOP tion of prostaglandin. COX-1 serves homeostatic functions in
many tissues, including the kidney, and inhibition can result in
Despite maintaining urinary pH at or above 7.0, DTs 24-hour a serious (e.g., up to 40%) decrease in glomerular filtration rate
level of methotrexate (MTX) was reported at 3.57 M, and leu- and potentially fatal renal insufficiency. Ibuprofen also inhibits
covorin (prophylactic cells rescue from excessive MTX toxicity) proximal tubule transporter proteins (MRP2 and MRP4) used by
was increased from 15 mg to 50 mg IV every 6 hours. The phar- MTX, resulting in a lower renal tubular efflux of MTX. COX-2
macist reviewed DTs medications and, noting that he was tak- selective inhibitors (sulfonamide or sulfone-containing diaryl-
ing ibuprofen around the clock for headache, discontinued that heteroaromatic structures) do not alter MTX renal clearance
medication. Subsequently, DLs 48-hour level of MTX dropped to kinetics, but COX-2 selective inhibitors are not used to treat
an acceptable 0.03 M, and he was discharged. headache.
MTX is approximately 50% bound to serum proteins;
Chemical Analysis its 7-hydroxy metabolite is 93% protein bound with a small
Victoria Roche and S. William Zito volume of distribution. Ibuprofens serum protein binding
approaches 99%. All drugs are anionic in the bloodstream, con-
The stronger of methotrexates two glutamate COOH groups tributing to their ability to compete for limited protein binding
(-COOH) would exist predominately in water-soluble anionic sites. Displacement of MTX and its cytotoxic 7-hydroxy metabo-
conjugate base form at DLs urinary pH (i/u = 1587/1 at pH 7.0). lite from serum proteins secondary to ibuprofen co-therapy can
However, DLs chronic use of ibuprofen is compromising his result in abnormally high blood levels of free drug. Because ibu-
renal function and allowing MTX to rise to toxic levels in the profen also inhibits the urinary excretion of MTX, life-threatening
blood, necessitating additional rescue therapy with leucovorin. toxicity results. The toxicity is addressed by increasing the dose
Ibuprofen, an arylpropionic acid nonsteroidal anti- of leucovorin (rescue) and discontinuing use of the offending
inflammatory drug (NSAID), inhibits COX-1 and COX-2 NSAID.
H2N N N pKa 3.8 CH3 pKa 5.2

COOH
N COOH
N O
NH2 N C N (CH2)2- COOH CH2
H
CH3
pKa 4.8
Methotrexate Ibuprofen
CASE STUDY
Victoria Roche and S. William Zito
KV is a 48-year-old firefighter who has been called into action in full remission. He also experienced hypersensitivity to the
over the past several years fighting wildfires in Arizona, Montana, etoposide infusion, which, while initially managed with an infu-
Wyoming, and California. An increased incidence of testicular sion rate adjustment, corticosteroids, and antihistamines, pro-
cancer has been noted among men in KVs line of work, and he gressed to the point where epinephrine was required to reverse
received this difficult diagnosis a little more than a month ago. bronchospasm.
Fortunately his cancer is still in the early stages (stage IB). The oncologist is consulting with you about appropriate
KVs oncologist has elected the BEP regimen, which com- next steps that could be taken to develop a chemotherapy regi-
bines bleomycin, etoposide, and cisplatin. He has been through men for KV that would give him the best chance for recovery
one round of chemotherapy but is not responding as well as with a high quality of life. A decision is made to change both
anticipated. KVs oncologist suspects intrinsic resistance to cis- the etoposide and the platinum complex in the regimen. Which
platin. In addition, KV read on the internet about the possibil- of the structures in each pair of molecules below might be
ity of hearing loss with this platinum coordination complex, viable alternatives to accomplish the desired outcome? If you
and he has verbalized his fear that this permanent toxic effect made any of these alterations in therapy, would you also rec-
could keep him from returning to work once he is (hopefully) ommend the coadministration of either compounds A or B?

OH
H H N
CH2-CH3
H3C O H3C
O O
O O
HO O HO O N
O
HO H HO H
H N
O O H3CO2C
O O
O O H4 CH2CH3
H H 3
O O H3CO N OAc
H
CO2CH3
H3C OH
H3CO OCH3 H3CO OCH3
OH OPO3H2
Etoposide Etoposide alternative 1 Etoposide alternative 2
MgSO4
H2N NH2 H3N NH3
H3N NH3
Pt
A
Pt Pt
Cl Cl O O O O O
H
O C C O H2N (CH2)3 N (CH2)2 S P OH
O O OH
Cisplatin Cisplatin alternative 1 Cisplatin alternative 2 B
1. Conduct a thorough and mechanistic SAR analysis of the 2. Apply the chemical understanding gained from the SAR
three therapeutic options in the case. analysis to this patients specific needs to make a thera-
peutic recommendation.
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Chapter

Drugs Covered in This Chapter

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Gefitinib Nilotinib Temsirolimus

INTRODUCTION programmed cell death (apoptosis). In cancer, these

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Renal cell cancer VHL dysfunction

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TABLE 37.2 Oncogenic Markers and Therapeutic Strategies in Selected Cancers

Breast cancer HER2 amplification Poor Aggressive chemotherapy,

Acute myelogenous t(8;21) or inv(16) Good Standard chemotherapy

Acute lymphocytic leukemia bcr-abl rearrangement Poor Bone marrow transplantation

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Lemke_Chap37.indd 1203 12/20/2011 2:24:52 PM

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Signs and Symptoms

Men Women Men Women Men Women

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Cancer Chemotherapy colony-stimulating factor, which boosts the ability of

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This is the time when DNA is unwinding and exposing its R

functional groups will encounter the electrophilic anti-

FIGURE 37.1 DNA destruction through nitrogen mustardmediated alkylation.

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this is happening in a tumor cell, the therapeutic goal has H

in a tumor cell or a healthy cell, as soon as the aziridinium

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Nitrogen mustards and aziridine-mediated alkylators:

O O O Miscellaneous DNA alkylators:

FIGURE 37.3 DNA cross-linking agents.

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agents (e.g., the anticancer monoclonal antibody ritux-

FIGURE 37.5 Cyclophosphamide metabolism.

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electrophilic by-product alkylates cysteine (Cys) residues O

occurs extracellularly, the aldophosphamide is still able Mesna

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Thiotepa Thiotepa, a tertiary aziridine, is less reac-

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Vinyl carbocation Acetaldehyde

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Streptozocin The glucopyranose moiety of streptozocin

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H2N N N intermediates of CYP450-mediated metabolism can also

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CH3SO2 O (CH2)4 O SO2CH3 CH3SO2 O (CH2)4 guanine-DNA

FIGURE 37.13 Busulfan-mediated DNA alkylation.

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H2O Resistance to cisplatin therapy can be intrinsic in

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Irinotecan hydrochloride (Camptosar) Topotecan hydrochloride (Hycamtin)

H3CO OCH3 H3CO OCH3 H3CO OCH3

Etoposide (VePesid) Etoposide phosphate Teniposide hydrochloride

FIGURE 37.17 Camptothecins and epipodophyllotoxins: topoisomerase poisons.

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CH3 a carbene-generating diazirine photoaffinity label (71),

anthracyclines (see antineoplastic antibiotics). TopII H3C O

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H H and vomiting, most noticeable with the oral dosage form,

Catechol metabolite Orthoquinone metabolite Teniposide Teniposide is used in combination with

Cancer Foye's Principles of Medicinal Chemistry-1219-1286

Cancer Foye's Principles of Medicinal Chemistry-1219-1286