Anticancer drugs

Outline of this lecture

Introduction to cancer
General concept of anti-cancer drugs
Chemotherapy: CCS drugs
Chemotherapy: CCNS drugs
Targeted therapy and New drugs
Quiz


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Diagnosis (?)
 Hallmarks of Cancer

Cell. 2000 Jan 7;100(1):57-70.

 Treatment
Surgery and/or radiation
Chemotherapy
Immunotherapy
Targeted therapy
Immunotherapy?
Adjuvant chemotherapy


Basic and Clinical Pharmacology, 12th Ed., 2012

Overview of anticancer drugs
 Adverse effects of chemotherapy

Thrombocytopenia: recombinant IL-11 (oprelvekin, Neumega)

Platelet transfusion
Neutro (Leuko)penia: GCSF (granulocyte colony-stimulating factor)
(Filgrastim) and Sargramostim (GM-CSF)
Effects on the GI tract and bone marrow are often dose-limiting adverse
effects
Dose-limiting: Describes side effects of a drug or other treatment that are
serious enough to prevent an increase in dose or level of that treatment.
Pharmacology and the Nursing Process, 7e, 2014
CCS drugs: Antimetabolites,
natural products and others
 Antimetabolites
Antifolates: Methotrexate (MTX)
Pharmacological properties
Pharmacological properties
Clinical uses (1)
 Clinical uses (2)
MTX is administered by the
intravenous, intrathecal, or oral
route.
Renal excretion is the main route of
elimination and is mediated by
glomerular filtration and tubular
secretion. As a result, dose
modification is required in the setting of
renal dysfunction. Care must also be
taken when MTX is used in the
presence of drugs such as aspirin,
NSAIDs, penicillin, and cephalosporins,
as these agents inhibit the renal
excretion of MTX.
Leucovorin (a rescue drug and
antidote) for MTX
 Adverse effects and contraindications
Adverse effects
Myelosuppression
Mucositis
Diarrhea
Contraindications
Teratogenic
Combined with misoprostol (PGE1 analog) to
induce early abortion
 Antimetabolites
Fluoropyrimidines: 5-Fluorouracil (5-FU)
 Mechanism of action
5-FU is inactive in its parent form. One of its
metabolites is 5-fluoro-2-deoxyuridine-5-
monophosphate (FdUMP), forming a
covalently bound ternary complex with the
enzyme TS. This results in inhibition of DNA
synthesis through thymineless death.
5-FU is converted to 5-fluorouridine-5-
triphosphate (FUTP), which is then
incorporated into RNA, where it interferes
with RNA processing and mRNA
translation.
5-FU is also converted to 5-
fluorodeoxyuridine-5-triphosphate (FdUTP),
which can be incorporated into cellular DNA,
resulting in inhibition of DNA synthesis
and function.
 Therapeutic uses

FOLFOX (5-FU + Oxaliplatin + Leucovorin)
GI toxicity(ulceration) IV administration
Because of its extremely short half-life by IV administration, on the
order of 10~15 minutes, infusional schedules of administration have
been generally favored over bolus schedules.
AE: , nausea, diarrhea, neurotoxicity and bone marrow
suppression . (hand-foot syndrome)
(palmar plantar erythrodysesthesia (PPE))


 Antimetabolites
Deoxycytidine analogs: Cytarabine and Gemcitabine

Cytarabine (ara-C) is an S phase-specific antimetabolite

that is converted by deoxycytidine kinase to the 5-
mononucleotide (ara-CMP) and then ara-CTP. Ara-CTP
competitively inhibits DNA polymerase, thereby resulting
in blockade of DNA synthesis and DNA repair,
respectively. This metabolite is also incorporated into
RNA and DNA. Incorporation into DNA leads to Inhibits ribonucleotide
interference with chain elongation and defective ligation reductase (for dCTP
of fragments of newly synthesized DNA. synthesis)

Cytarabine
syndrome:
fever, muscle
and bone
pain
 Bleomycin
A mixture of different metal chelating
glycopeptide
MOA: scission of DNA
Causes accumulation of cells in the G 2 phase
of the cell cycle.
Therapeutic uses: Hodgkins and non-Hodgkins
lymphoma, germ cell tumor and head and neck
cancer
Toxicity:
1. (1-10%)(8%)(50%)
(50%)(50%)allergic rx,
fever, chills, and hypotension (acute)
2. Pulmonary fibrosis (delayed) (Bleomycin lung)
Natural products

Tubulin-binding Agents
Vinca alkaloids
 Vinca alkaloids
Vincristine and Vinblastine
Both are metabolized by cytochrome P-450
Despite their similarities, they have a strikingly different spectrum of
clinical activity and safety profile.
Vincristine (VXOncovin)
1. ALL (in children).
2. (paralytic ileus), myelosuppression
Vinblastine (VBL)
1. Nausea and vomiting, myelosuppression
Paclitaxel (Taxol)
 Clinical uses and adverse effects of paclitaxel
Paclitaxel (semisynthetic) and docetaxel
Clinical uses:
1. Advanced ovarian cancer and metastatic breast cancer
2. (Non)-Small-cell lung cancer, prostate, bladder cancer, head
and neck cancer
Adverse effects Castor oil : Cremophor EL
Acute- Nausea and vomiting, hypotension, hypersensitivity (due
to its oil solvent, premedicated with a steroid, H1 and H2 antagonists)
albumin-bound paclitaxel (can interact with gp60)
Delayed- myelosuppression and peripheral sensory neuropathy
Neutropenia -> GCSF (filgrastim)
Epipodophyllotoxin: Etoposide

podophyllum

epipodophyllotoxin
()
 Etoposide (VP-16)
Topoisomerase-active Drugs
Clinical uses:
Oral and IV form
IV form (in a hydroalcoholic diluent
-> hypotension): can be improved
by water-soluble form.
1. Lung cancer
2. Non-Hodgkins lymphoma
3. Gem cell tumor
4. Gastric cancer
PEB: Cisplatin, etoposide, and
bleomycin

Adverse effects:
Acute nausea and vomiting,
hypotension
CCNS drugs: Alkylating agents
and antibiotics
 Characteristics of Alkylating Agents
Alkylation of DNA damage of DNA
Have a broad spectrum of anti-tumor activity and
immunosuppression
Active against proliferating and nonproliferating cells
Cause dose-limiting myelosuppression
Pulmonary fibrosis
Cytotoxic, mutagenic and carcinogenic (e.g. Procarbazine)
lead to a secondary malignancy such as
leukemia (leukemogenic effect)
Structures of major classes of alkylating agents
Alkylating Agents
Mechanism of action
of alkylating agents

MOA: cell-cycle
nonspecific
1. Alkylation
2. Depurination
3. Miscoding mutation
 Mechlorethamine
Prototype, but the use of this drug has
declined recently
Therapeutic uses
used primarily in the treatment of Hodgkins and
non-Hodgkins lymphoma
MOPP: Mechlorethamine + Oncovin
(vincristine) + Prednisone + Procarbazine
Adverse effects: nausea and vomiting
extravasation infiltrated with isotonic
sodium thiosulfate (1/6 M)
 Cyclophosphamide (Endoxan)
Cyclophosphamide (Endoxan)
(non-)Hodgkins lymphomaCLL
neuroblastoma
Used as an immunosuppressant
alopecia ()

Prevented by coadministration of the sulfhydryl-
releasing agent (Mesna)
Chlorambucil: CLL and non-Hodgkins lymphoma
Melphalan (PAM)Multiple myeloma, breast cancer,
ovarian cancer
 (Alkylating agents)
(Nitrosoureas)
Carmustine (BCNU) and Lomustine (CCNU)
BBB
(Temozolomide for gliomas and astrocytomas)
Busulfan CMLskin
pigmentation and adrenal insufficiency
Thiotepa (Tespamine) breast, ovarian
and superficial bladder cancer

Degradation of carmustine (BCNU) with generation of
alkylating and carbamoylating intermediates
 Nonclassic alkylating agents:
Temozolomide and Dacarbazine
Temozolomide, a triazene agent, has been approved
for use against glioblastomas and anaplastic
astrocytomas. It is also used in metastatic melanoma.

Dacarbazine is an alkylating agent that must undergo

biotransformation to an active metabolite. Similar to
other alkylating agents, the cytotoxic action of
dacarbazine has been attributed to the ability of its
metabolite to methylate DNA on the O6 position of
guanine. Dacarbazine has found use in the treatment
of melanoma and Hodgkin lymphoma.
 Platinum compounds
Cisplatin , Carboplatin and Oxaliplatin
MOA: similar to that of the alkylating agents
Clinical uses:
Non-small and small lung cell cancer, breast, bladder cancer, head
and neck cancer, (combined with cyclophosphamide), germ cell
cancer (PEB) and testicular cancer (cisplatin and etoposide)
Oxaliplatin: shows excellent activity against advanced colorectal
cancer.
Adverse effects
Anthracyclines: Doxorubicin, daunorubicin, ,
epirubicin and idarubicin

(Adriamycin)
 Mechanism of action of ~rubicins
(1) Inhibition of topoisomerase II
(2) High-affinity binding to DNA
through intercalation, with
consequent blockade of the
synthesis of DNA and RNA, and
DNA strand scission
(3) Generation of semiquinone
free radicals and oxygen free
radicals through an iron-
dependent, enzyme-mediated
reductive process
(4) Binding to cellular membranes
to alter fluidity and ion transport
 Therapeutic uses
Doxorubicin: for the treatment of sarcoma, carcinoma
(breast and lung), Hodgkins and non-Hodgkins lymphoma,
thyroid cancer
Daunorubicin: for acute lymphocytic and myelocytic
leukemias (AML & ALL)
Toxicity:
Stomatitis, nausea and red urine (acute)
Cardiac damage (Heart failure and dysrhythmias)
(delayed toxicity) liposomal-encapsulated
doxorubicin (toxicity and duration ) for ovarian
cancer and with bortezomib for multiple myeloma
 L-Asparaginase (Elspar)
Pegaspargase: pegylated asparaginase
L-Asparaginase
MOA: L-Asparagine
Asparaginase Aspartic acid
Adverse effects:
1. From E. coli: hypersensitivity fever, chills, nausea
and vomiting
2. Severe: bronchospasm, respiratory failure and
hypotension
3.
Acute lymphocytic leukemia
 Steroid hormones and their antagonists

Prednisone
Lympholytic effects
Suppresses mitosis in
lymphocytes

Therapeutic uses:
in pt with acute
lymphocytic leukemia, (non-)
Hodgkins lymphomas
 Cancer cell
resistance
1. Mutations in the p53
tumor suppressor gene.
2. Defects in the mismatch
repair enzymes.
3. Multidrug resistance
(MDR1) due to ATP-
dependent pumping of
drugs out of the cell in
the presence of P-
glycoprotein
 used in the first-line treatment of
Hodgkin lymphoma

New drugs and targets:

Targeted therapy
 Promotion of tumor growth by
Neovascularization (Angiogenesis)

N Engl J Med 333: 1757-1763, 1995

Strategy 1: angiogenesis as a
therapeutic target
Strategy 2:
Tumor markers as a therapeutic target
1. Target specific tumor (surface) marker
2. Target growth factor signaling pathways
DRUGS TARGETING ANGIOGENESIS
 Antiangiogenesis agent
Bevacizumab (Avastin) ()
Anti-VEGF-A monoclonal Ab
A first-line drug against metastatic colorectal cancer
Infused Intravenously
Adverse effects:
Hypertension, stomatitis (), diarrhea.
Other drugs: Ziv-aflibercept, Sorafenib, Sunitinib, & Pazopanib
DRUGS TARGETING TUMOR
MARKERS
Protein kinase inhibitors

Gefitinib
Gefitinib (Iressa) and erlotinib (Tarceva)
Gefitinib (Iressa)
1. Small molecule that target the EGF receptor
3. For the treatment of non-small cell lung cancer
4. Adverse effect: (48%)(43%) interstitial
lung disease (rare but fetal)
Erlotinib (Tarceva)
Adverse effect:

39%
55%
(2-11%, 2-5)gefitinib30%
()10%erlotinib

 Tyrosine Kinase Inhibitors :
Imatinib (Glivec), Dasatinib, and Nilotinib
A tyrosine kinase inhibitor
Occupy the kinase pocket
Orally active
Clinical uses:
1. Used as a first-line drug for CML
2. GI stromal tumor
Adverse effects:
GI distress, fluid retention, edema, thrombocytopenia,
neutropenia and potential drug interaction [(-)P450]
Other drugs: 1. Dasatinib (binds to the active and inactive
conformations of the Abl kinase domain
2. Nilotinib (2nd generation, 20~50 fold than imatinib)
Mechanism of action of ~tinibs

December 15, 2008; Blood: 112 (13).

Translation of the Philadelphia chromosome into therapy for CML
 Tratuzumab (Herceptin)
HER2 (human epidermal growth factor receptor 2) is
seen in 25-30% of patients.
A recombinant DNA-produced, humanized
monoclonal Ab, targeting the extracellular domain
of the HER2 growth receptor.
Used in patient with metastatic breast cancer.
Adverse effect:
Congestive heart failure (CHF)

Cetuximab and Panitumumab

(Abs targeting EGFR): for
metastatic colorectal cancer
 Rituximab (Mabthera)
A chimeric mAb directed against the CD20 antigen on
B lymphocytes.
MOA: complement and Ab-dependent, cell-mediated
cytotoxicity of the B cells.
For lymphoma and chronic lymphocytic leukemia
[combined with CH(E)OP]
Pharmacokinetics: IV infusion
Adverse effects: severe and fatal
Hypotension, bronchospasm, angioedema, chills and
fever. Tumor lysis syndrome renal failure.
 B cell maturation

Edwards et al. Nature Reviews Immunology 6, 394403 (May 2006) | doi:10.1038/nri1838

 Radioimmunoconjugates
Radioimmunoconjugates provide targeted delivery of
radionuclides to tumor cells. 131Iodine (131I) is a favored radioisotope
because it is readily available, relatively inexpensive, and easily
conjugated to a monoclonal antibody. The particles emitted by 131I
can be used for both imaging and therapy, but protein-iodine
conjugates have the drawback of releasing free 131I and 131I-
tyrosine into the blood, and thus present a health hazard to
caregivers, family, and others in contact with the patient.
The 90Y-emitter has emerged as an attractive alternative to 131I,
based on its higher energy and longer path length. These features
suggest that it may be more effective in tumors with larger
diameters. It also has a short t1/2 and remains conjugated, even after
endocytosis, providing a safer profile for outpatient use.
Other Targeted And Miscellaneous
Drugs (1)
 Proteasome inhibitors
Bortezomib was first approved for
use in relapsing or refractory multiple
myeloma and is now widely used as
first-line therapy. This agent is thought
to exert its main cytotoxic effects
through inhibition of the 26S
proteosome, resulting in down-
regulation of the nuclear factor
kappa B (NF-B) signaling pathway,
which is felt to be a major signaling
pathway for this disease. Of note,
inhibition of NF- B has also been
shown to restore chemosensitivity.
Based on this mechanism of action,
further efforts have focused on
developing bortezomib in various
combination regimens.

Nature Reviews Drug Discovery 8, 33-40 (January 2009)

Thalidomide and Lenalidomide

(Dermatology Online Journal, 2009, 15(6): 15

Thalidomide has been reintroduced to

clinical practice as an oral agent for the
management of erythema nodosum
leprosum (ENL) and in other disease
settings, most notably Multiple myeloma.

Lenalidomide (REVLIMID) is approved

for treatment of transfusion-dependent
anemia due to low- or intermediate-risk
myelodysplastic syndromes associated
with the 5q cytogenetic deletion, with or
without additional cytogenetic
abnormalities.
Adverse effect: peripheral neuropathy
Thalidomide catastrophe
Other Targeted And Miscellaneous
Drugs (2): Supplementary slides
(For cutaneous T-
cell lymphoma)

(For renal cancer)

 Histone deacetylase Inhibitors
Epigenetic processes are implicated in cancer causation and progression. The
acetylation status of histones regulates access of transcription factors to DNA
and influences levels of gene expression. Histone deacetylase (HDAC) activity
diminishes acetylation of histones, causing compaction of the DNA/histone
complex. HDAC inhibitors (HDI) block this action and can result in
hyperacetylation of histones, thereby affecting gene expression.

Nature Reviews Drug Discovery 1, 287-299 (April 2002)

 mTOR inhibitors
Rapamycin (sirolimus) is a fungal
fermentation product that inhibits the
proper functioning of a
serine/threonine protein kinase in
mammalian cells eponymously
named mammalian target of
rapamycin, or mTOR, an effector PI3
kinase signaling. The
PI3K/PKB(Akt)/ mTOR pathway
responds to a variety of signals from
growth factors (e.g., insulin,
interleukins, EGF) that modulate cell
growth, translation, metabolism,
and apoptosis.
 Questions
1. taxol(A)
vincristine (B) paclitaxel (C) doxorubicin (D) dactinomycin
2. (A) vinblastine (B) doxorubicin (C)
cyclophosphamide (D)bleomycin
3. (A) doxorubicin (B) bleomycin (C) paclitaxel
(D) vincristine
4. folic acid analog
(A) fluorouracil5-FU (B) cyclophosphamide (C) vincristine (D) methotrexate
5. methotrexate(A)
leucovorin (B) glucose (C) vitamin B (D) vitamin C
6. DNAS phase(A)
cyclophosphamide (B) ara-C (C) paclitaxel (D) cisplatin
7.
(A) mechlorethamine (B) chlorambucil (C) busulfan (D) cyclophosphamide
8. (A) 5-fluoro-uracil
(B) cyclophosphamide (C) bleomycin
(D) methotrexate
9. S(A) cyclophosphamide
(B) bleomycin (C) vincristine (D) 5-fluorouracil
10. topotecan(A) (B)
(C) cisplatinpaclitaxel (D)

 Questions
1. interleukin-11 oprelvekin
chemotherapy(A)Vomiting (B)Severe thrombocytopenia
(C)Alopecia(D)Diarrhea
2.
thymidylate synthase(A)methotrexate (B)5-FU5-fluorouracil
(C)cyclophosphamide (D)vinca alkaloidsvincristine
3. vincristine methotrexate (A)
(B)DNA repair (C)P-glycoprotein transporter (D)Glucose-6-
phosphate dehydrogenase
4. (A)Doxorubicin
(B)Trastuzumab (C) Anastrozole (D)Fluoxymesterone
5. 5-fluorouracil (A)DNA DNA
(B)dihydrofolic acid (C)thymidylate synthase
(D)DNA polymerase
6. Hodgkins disease (A)ABVD(adriamycin,
bleomycin, vinblastine, dacarbazine) (B)CMF(cyclophosphamide, methotrexate, 5-
fluorouracil) (C)PVC(procarbazine, vincristine, CCNU) (D)BEP(bleomycin, etoposide,
cisplatin)
7. Topoisomerase (A)Doxorubicin
(B)Mitomycin C (C)Etoposide (D)Daunorubicin
8. (acute promyelocytic leukemia)
(A)Adriamycin (B)Retinoic acid (C)Cyclophosphamide (D)Folic acid