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CHEMOTHERAPEUTIC DRUGS

CANCER CHEMOTHERAPY

Alkylating Agents
- Cell Cycle Nonspecific
- Alkylate nucleophilic groups on DNA bases (N7 guanine)
- Crosslinking, abnormal base pairing, DNA strand breakage
Cyclophosphamide - Hepatic biotransformation needed
- Non Hodgkins lymphoma, breast/ovarian CA,
neuroblastoma
- Hemorrhagic cystitis (acrolein) hydrate, give
mesna to reduce incidence
Mechlorthamine - Hodgkins disease
- Toxcicity: vesicant actions
Cisplatin/Carboplatin - Testicular CA (bladder, lung, ovary CA)
- Neurotoxic (peripheral neuritis, acoustic nerve
damage) and nephrotoxic
- Carboplatin less nephrotoxic, greater
myelosuppresant action
- rescue drug: Amifostine
Procarbazine - forms H2O2, DNA strand scission
- component for Hodgkins
- myelosuppresant, GI irritation
- MAO inhibition, disulfirma like reaction,
leukemogenic
Busulfan - CML
- Cause adrenal insufficiency, pulmonary fibrosis,
skin pigmentation
Carmustine (BCNU)
and Lomustine
(CCNU)
- Highly lipid soluble
- Adjuncts in the management of brain tumors

Antimetabolites
-structurally similar to endogenous compounds
-cell cycle specific primarily on phase S
-cytotoxic, immunosuppresant
Folic acid antagonist - Methotrexate
Purine - Mercaptopurine, thioguanine
Pyrimidine - Fluorouracil, Cytarabine

Methotrexate
- Inhibit dihydrofolate
reductase
- Decrease thymidylate,
purine and AA synthesis
- Does not penetrate CNS
- Clearance dependent on renal function
- Choriocarcinoma, acute leukemias,
non Hodgkins/cutaenous T cell
lymphomas, breast CA
- Also used in rheumatoid arthritis and
ectopic pregnancy
- abortifacient
Toxicity:
- myelosuppression
- mucositis
- folinic acid (leucovorin) reduces toxic action on normal cells
leucovorin rescue
- long term: hepatotoxicity and pulmonary infiltrates/fibrosis

Mercaptopurine (6-MP) and Thioguanine (6-TG)
- activated by HGPRTase and
inhibit enzymes in purine
metabolism
- allopurinol inhibit 6-MP metabolism
(toxic levels may be reached rapidly)
- acute leukemias, CML
Toxicity:
- dose limiting myelosuppression
- hepatic dysfunction

Cytarabine (IV)
- inhibit DNA polymerase - of all the antimetabolites, is the
most specific for the S phase
- treatment for acute leukemias
Toxicity:
- GI irritation and myelosuppression
- neurotoxicity at high dose (cerebellar dysfunction and
peripheral neuritis)

Fluorouracil (5-FU)
- inhibits thymidylate
synthase
- thymineless death of cells
- Bladder, breast, colon, head and
neck, liver, ovarian CA
- Topically for keratoses and
superficial BCC
Toxcity:
- GI distress, myelosuppression, alopecia

Plant Alkaloids
- Cell cycle specific

Vinblastine/ Vincristine (IV)
- Block formation of mitotic
spindle (prevent microtubule
assembly)
- Act primarily on M phase
- Vincristine: Acute leukemias,
lymphomas, Wilms tumor,
choriocarcinoma
- Vinblastine: GI distress, alopecia,
bone marrow suppression
Toxicity:
- Vincristine: neurotoxic actions (areflexia, peripheral neuritis,
paralytic ileus)
- Vinblastine: GI distress, alopecia, bone marrow suppression

Etoposide and Teniposide
- Interact with topoisomerase II,
degrade DNA
- Inhibits electron transport
- Most active in late S and early G2
- Lung (small cell), prostate,
testicular CA
Toxicity: GI irritant, alopecia, myelosuppression

Paclitaxel and Docetaxel (IV)
- Interfere with mitotic spindle
- Prevent microtubule disassembly
- Advanced breast and
ovarian CA
Toxicity: neutropenia, thrombocytopenia, high incidence of peripheral
neuropathy, hypersensitivity reactions
Docetaxel: neurotoxicity and bone marrow depression

Antibiotics
Doxorubicin and Danorubicin (IV)
- Intercalate between base pairs
- Inhibit topoisomerase II
- Generate free radicals
- Block RNA/DNA synthesis
- Cause DNA strand scission
- Cell cycle NON specific
- Doxorubicin: Hodgkins,
myelomas, sarcomas,
breast, endometrial, lung,
ovarian, thyroid
- Daunorubicin: mainly for
acute leukemias
- Idarubicin: AML
Toxicity
- Bone marrow suppression, GI distress, severe alopecia
- Cardiotoxicity protective effect by Dexrazoxane
- Rescue drug Dacrazone

Bleomycin (IV)
- Generates free radicals
- Bind to DNA, cause strand
- Hodgkins disease,
testicular CA
breaks
- Inhibit DNA synthesis
- Cell Cycle specific: G2 phase
- Lymphomas, SCC
Toxicity:
- Pulmonary dysfunction (pneumonitis, fibrosis)- dose limiting
- Hypersensitivity, mucocutaneous reactions

Dactinomycin (IV)
- Binds to dsDNA
- Inhibits DNA dependent RNA
synthesis
- Cell cycle NON specific
- Excreted in bile
- Melanoma, Wilms tumor
- Toxicity: myelosuppression, skin reaction, GI irritation

Mitomycin (IV)
- Metabolized by liver enzymes
to form alkylating agent
- DNA crosslinking
- Cell cycle NON Specific
- Acts against hypoxic tumor
cells
- Combination regimen for
cervix, stomach, pancreas,
lung adenocarcinoma
- Toxicity: severe myelosuppression
- Toxic to heart, liver, lung, kidney

Hormonal Anticancer Agents
Glucocorticoids
- Prednisone: most commonly used glucocorticoid in cancer
chemotherapy
- Leukemias/lymphomas
Sex hormone antagonists
Tamoxifen - selective estrogen receptor modulator
-used in receptor positive breast CA
-preventive effect for women with high risk of
breast CA
- activity in progesterone resistant endometrial CA
- Toxicity: N/V, hot flushes, vaginal bleeding,
venous thrombosis
Toremifene - Newer, used in advanced breast CA
Flutamide - Androgen receptor antagonist
- Prostatic CA
- ToxicitY: gynecomastia, hot flush, hepatic
dysfunction
Gonadotropin Releasing Hormone Analogs
Leuprolide,
Goserelin,
Nafarelin
- GnRH agonists
- Effective in prostatic CA
- Inhibit LH and FSH
- Leuprolide adverse effects:bone pain,
gynecomastia, hematuria, impotence, testicular
atrophy
Aromatase Inhibitors
Anastrozole,
Letrozole
- Inhibit aromatase (convert androgen to estrogen)
- Advanced breast CA, unresponsive to Tamoxifen
- Toxicity: N/D, hot flush, bone/back pain, dyspnea

Miscellaneous Anticancer Agents

Asparaginase
(IV)
- Depletes serum asparagines
- T cell auxotrophic cancers (leukemias, lymphomas)
- Hypersensitivities, acute pancreatitis, bleeding
Imatinib - Inhibits tyrosine kinase of Bcr-Abl, ckit
- Effective in CML, GIST
- Toxicity: diarrhea, myalgia, fluid retention
Interferons - Alpha interferons: hairy cell leukemia, early CML, T
cell lymphomas
- Toxicity: myelosuppression and neurologic
dysfunction
Monoclonal
antibodies
- Rituximab: non Hodgkins, low grade lymphomas
(hypersensitivity and myelosuppression)
- Trastuzumab: breast CA with Her2 Neu
overexpression (cardiotoxicity)

CHEMOTHERAPEUTIC DRUGS
IMMUNOPHARMACOLOGY

Immunosuppressive Agents
Corticosteroids
(glucocorticoids)
- Toxicity: adrenal suppression, growth
inhibition, muscle wasting,
osteoporosis, salt retention,
diabetogenesis
Cyclosporine
-bind to cyclophilin
- erratic bioavailability
- effective in other immune
diseases
- Cyclosporine : renal
dysfunction, neurotoxicity
(paresthesias 50%)
- Bind to immunophilin, inhibit
calcinuerin
- interfere with T cell function
- Cyclosporine solid organ transplant,
GVHD in marrow transplant
-Tacrolimus: liver and kidney transplant
-Sirolimus: kidney and heart transplant
- Toxicity: renal dysfunction,
hypertension, neurotoxicity,
hyperglycemia, hyperlipidemia,
cholelithiasis
- Sirolimus: more likely to cause
hypertriglyceridemia, hepatotoxicity,
diarrhea, myelosuppression
Tacrolimus and Sirolimus
-bind to FKBP
- Sirolimus: no effect on
cytokine production
Mycophenolate Mofetil
-converted to
mycophenolic acid
-inhibits IMD, de novo
purne pathway
-suppress both B/T
- Sole agent in kidney, liver, heart
transplant
- Toxicity: GI, myelosuppression
(neutropenia)
Azathioprine
- Transformed to
mercaptopurine
-inhibit enzymes in purine
metabolism
- Cytotoxic in early phase
of lymphoid proliferation
- Greater effect on T cells
- Autoimmune diseases,
immunosuppresion in renal homografts
- Toxicity: myelosuppression, GI
- Increased incidence of CA, affected by
allopurinol
Cyclophosphamide
-transformed to an
alkylating agent, cytotoxic
- Greater effect on B cells
- Effective in autoimmune diseases,
bone marrow transplant
- Does not prevent GVH in marrow
transplant
- Toxicity: hemorrhagic cystitis,
pancytopenia, GI, alopecia
Newer Immunosuppresants
Etanercept - Recombinant form of TNF receptor
- Binds TNF-a (decrease IL formation)
- Rheumatoid arthritis
Leflunomide - Inhibit dihydroorotic acid dehydrogenase
- Arrests lymphocytes in G1 phase
- Rheumatoid arthritis
- AE: alopecia, rash, diarrhea
Thalidomide - Sedative drug, teratogenic
- Suppress TNF production
- Leprosy, immunologic
- Wasting syndrome of AIDS patients
Alefacept - Targets CD2 receptor on T cell surface, inhibits Tcell
activation
- For psoriasis
- Dose dependent reduction in T cell

Antibodies as Immunosuppressants
Antilymphocytic globulin/
Antithymocyte globulin
- selectively block cellular immunity
- Suppress organ graft rejection
- Prevent GVH prior to marrow
transplant
- Toxicity: hypersensitivity
Rho Ig (RhoGAM) - Blocks primary immune response to
foreign cells
- Prevention of rh hemolytic disease of
newborn
Monoclonal antibodies
Muromonab
- Bind to CD3
- Block killing action of cytotoxic T cells
- Manage renal homograft rejection crisis
Daclizumab
- Bind to IL2

- Prevent activation of T cells by IL2
- Not used for acute rejection
- Renal transplants
Infliximab
- Target against TNF alpha
- Induces remissions in treatment
resistant Chrons disease
- Effective in IBD
Adalimumab
- Bind to TNF alpha
- Rheumatoid arthritis

Monoclonal antibody characteristics
MAB MOA Effect
Abciximab Gp IIb1/IIIa receptor
antagonist
Postangioplasty/ACS
Daclizumab Bind to IL2 receptor Renal transplant
Infliximab Target TNFa Chrons disease, RA
Muromonab Antibody to CD3 acute renal allograft
rejection
Palivizumab RSV surface protein RSV prophylaxis and tx
Rituximab CD20 antigen binding B cell NHL
Trastuzumab HER2Neu Breast CA

Immunomodulating Agents
Aldesleukin - Promote production of cytotoxic T cells
- Adjunctive treatment of Renal cell CA and
malignant melanoma
Interferons - IFN a-2a: hairy cell leukemia, CML, MM, Kaposis,
hepatitis B and C
- IFN B-1b: relapsing Multiple sclerosis
BCG - Immunization against TB
- Immunostimulant in superficial bladder CA
Thymosin - Di George syndrome

Mechanisms of Drug Allergy
Type I IgE mediated Penicillins and sulfonamides
Type II IgM/IgG Methyldopa (hemolytic anemia)
Hydralazine/Procainamide (SLE)
Quinidine (TTP)
Agranulocytosis
Type III Complement
fixing IgM/IgG
Serum sickness, vasculitis
Sulfonamide (Steven Johnson
syndrome
Type IV Cell mediated Topical application of drugs
Contact dermatitis
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