Pharm Chemo Drugs Sauld

DRUG ALKYLATING AGENTS Cyclophosphamide (Cytoxan)

MECHANISM - cross-linking of DNA via. covalent bond of alkyl group to DNA template (esp. rxn w/ 7nitrogen of guanine)

- oral - pro-drug, must 1st be metabolized by CYP450 into reactive cytotoxic metabolites i.e. acrolein

broad general activity solid tumors

Ifosfamide

- cross-linking of DNA (esp. rxn w/ 7-nitrogen of guanine)

- oral - activated by hydroxylation in liver (slower than cyclophosphamide) to dechlorinated metabolite and chloracetaldehyde (toxic metabolite)

testis, sarcomas solid tumors

- covalently binds DNA bases and disrupts DNA function via. crosslinking w/ platination

- nonenyzmatic inactivation intracellularly and in the bloodstream by sulfhydryl groups - highly covalently bound to proteins - >90% renal elimination of bound drug (adjust dose w/ renal insufficiency)

lung, testis, ovarian, bladder

PLATINUM BASED CMPDS Cisplatin

Carboplatin

- covalently binds DNA bases and disrupts DNA function via. crosslinking

ADME

USES

ovarian, lung, bladder

A/E - MYELOSUPPRESSION - mucosal damage to GI tract - HEMORRHAGIC CYSTITIS (via. acrolein metabolite) – keep pts well hydrated, administer Mesna - cardiotoxicity – monitor pts w/ ECGs - SIADH - ↓serum Na+ and CNS toxicity, can get seizures - MYELOSUPPRESSION - mucosal damage to GI tract - hemorrhagic cystitis (via. chloracetaldehyde metabolite) – keep pts well hydrated, administer Mesna - CNS toxicity w/ intrathecal administration, encephalopathy

- NEPHROTOXICITYw/ Mg wasting, hypokalemia – monitor electrolytes and maintain high urine flow - N/V – prophylactic antiemetics - PERIPHERAL NEUROPATHY, “stocking and glove” parasthesia, usually reversible - OTOTOXICITY, permanent - mild myelosuppression - rare hypersensitivity rxn - MYELOSUPPRESSION (esp. WBCs) - less N/V - less nephrotoxicity,

MISC not cell-cycle phase specific - resistance via. glutathione conjugation, enhanced DNA repair mechanisms or increased metabolism to inactive metabolites - acquired resistance does not imply cross resistance

- resistance via. enhanced DNA repair

- not cross resistant with cisplatin

neurotoxicity, ototoxicity

ANTIMETABOLITES Methotrexate (MTX)

5-Fluorouracil (5-FU)

Folic Acid Analog - inhibits dihydrofolate reductase (DHFR) Æ depletes reduced folates - inhibits DNA and RNA synthesis - mainly active during S-phase – give as 4 or 24 hour continuous infusion

Pyrimidine Analog of dUMP - inhibits thymidylate synthetase Æ depletion of thymidine - phase specific to G1 and S - inhibits DNA if given as continuous infusion - inhibits RNA if given as a bolus

Cytarabine

Pyrimidine Analog of dCTP/dCDP - inhibits nucleoside diphosphate reductase, DNA polymerase - S phase specific

Gemcitibine

Pyrimidine Analog - inhibits ribonucleotide reductase Æ DNA strand termination - sensitizes cells to radiation therapy

NATURAL PRODUCTS

- oral, intrathecal, IV, IM - requires active transport into cell - metabolized to polyglutamates in normal and malignant tissues - doesn’t cross BBB (can administer intrathecally) - binds plasma prots but is displace by aspirin and other drugs - eliminated intact in urine; urine alkalinization promotes excretion (limited solubility in acidic environment) - IV (topical for skin Ca) - prodrug that must be converted to nucleotide form (F-dUMP) by liver - crosses BBB - metabolized in liver - excreted in lungs and urine

bladder, lymphoma, brain tumors, osteosarcoma, childhood ALL

- IV or intrathecal - must be phosphorylated to triP active form in the tumor - rapidly inactivated by hepatic cytidine deaminase in the plasma therefore administered as a continuous IV infusion - musb be phosphorylated to mono-P

acute leukemias

- slow growing solid tumors breast, all GI (esp. colon), bladder, breast, head & neck premalignant lesions (topical)

bladder, pancreas, lung

- myelosuppression - mucositis, GI epithelial denudation - nephrotoxicity (prevent w/ hydration) - pneumonitis - neurotoxicity (if intrathecal or high doses) - hepatotoxicity - teratogenic

- MYELOSUPPRESSION (if bolus) - MUCOSITIS (w/ continuous infusion) & hand-foot syndrome of erythematous desquamation - cardiac toxicity - hepatic toxicity - diarrhea, stomatitis - MYELOSUPPRESSION - alopecia - N/V - neurotoxic (high doses)

- mild myelosuppression - mild flu-like sxs - rashes

- rescue BM and mucositis w/ Leucovorin - do not administer to pts w/ poor renal fcn; monitor creatinine clearance - resistance via. increased DHFR prodxn or deccreased affinity for MTX or decreased cellular uptake - inhibits cell-mediated immune rxns – used at low doses for rheumatoid arthritis, Crohn’s dz - cytotoxicity increased by Leucovorin in tx of colon cancer; also increases toxicity - resistance via. decrease in drug activation or use of alternate pathways - resistance via. decrease in drug activation, increase in drug inactivation, use of alternate pathways

Vinblastine

- binds tubulin and prevents microtubule assembly Æ arrest in metaphase

- IV - metabolized in liver - excreted in bile

Vincristine

- binds tubulin and prevents microtubule assembly Æ arrest in metaphase

Vinorelbine

- binds tubulin and prevents microtubule assembly Æ arrest in metaphase - binds tubulin and prevents microtubule depolymerization Æ no mitosis

- IV - metabolized in liver - excreted in bile - longest half life of vincas Æ lowest max tolerated dose - IV, never intrathecal b/c fatal - metabolized in liver - excreted in bile

Paclitaxol (Taxol)

Hodgkin’s and nonHodgkin’s lymphoma, breast - w/ bleomycin for testicular tumors ALL, Hodgkin’s and nonHodgkin’s lymphoma

- limited water solubility therefore formulated with ethanol - hepatic metabolism and biliary excretion

ovary, breast, bladder, prostate

Docitaxel (Taxotere)

- binds tubulin and prevents microtubule depolymerization Æ no mitosis

- hepatic metabolism and biliary excretion

breast, prostate

Etoposide

- inhibits topoisomerase II Æ DNA strand breakage - arrests cells in S and early G2

- IV or parenteral

lung, testis, lymphomas

Irinotecan

- targets topoisomerase I and

-prodrug must be converted to

colon

- MYELOSUPPRESSION

- no cross resistance b/w vinca alkaloids - resistance via. MDR drug efflux pump

- PERIPHERAL NEUROPATHY - SIADH

- minimal myelosuppression - resistance via. MDR drug efflux pump

- MYELOSUPPRESSION - mild neuropathy

- newer and less toxic

- MYELOSUPPRESSION, esp. neutropenia and thrombocytopenia - alopecia - N/V - sensory neuropathy - PERIPHERAL NEUROPATHY - ANAPHYLAXIS - myalgias -cardiac toxicity - myelosuppression, esp. neutropenia and thrombocytopenia - alopecia - N/V - sensory neuropathy - less neurotoxicity - capillary leak syndrome Æ pleural effusion and periph edema - MYELOSUPPRESSION - N/V - alopecia - mucositis - 2ndary leukemias - DELAYED ONSET

- resistance via. mutations in alpha or beta subunits of tubulin - anaphylactic rxn avoided by prophylaxis w/ antihistamine (i.e. diphenhydramine/Benadryl + steroid/hydrocortisone

- resistance via. mutations in alpha or beta subunits of tubulin - anaphylactic rxn avoided by prophylaxis w/ antihistamine (i.e. diphenhydramine/Benadryl + steroid/hydrocortisone - resistance via. MDR drug efflux pump

causes double stranded DNA breaks

active metabolite

Doxorubicin (Adriamycin)

Anthracycline antibiotic - inhibits RNA synthesis - binds dsDNA and intercalates b/w GC pairs - inhibits function of topoisomerase II Æ DNA damage - free radical formation via. lipid peroxidation - interacts w/ cell membrane

- IV - elimination via. liver, bile, aglycone formation and others

broad general activity (no colon, lung)

Bleomycin

Antibiotic - nicks DNA and inhibits DNA ligase Æ DNA fragmentation - free radical formation - most active during G2 and M phases

- IV, IM, SQ - renal elimination

Imatinib (Gleevec)

tyrosine kinase inhibitor - inhibits BCR-ABL of CML chimeric monoclonal Ab - binds CD20 antigen on B lymphocytes Æ lysis of tumor cells Monoclonal Ab - binds HER2 receptor expressed by some breast cancer celss

- oral

-squamos cell carcinomas of the head, neck, skin, esophagus and GU tract; Hodgkin’s and nonHodgkin’s lymphoma - w/ vinblastine or etoposide for testicular tumors CML

- blocks estrogen-stimulated progesterone receptor synthesis, 52K protein synthesis, DNA polymerase activity, tritiated thymidine incorporation - blocks cells in mid-G1 - binds estrogen receptor and promotes tight assn to nucleus

- oral - hepatic metabolism

Rituximab

Trastuzumab (Herceptin) BIOLOGICALS Tamoxifen

DIARRHEA - myelosuppression - N/V - alopecia, low fevers - CARDIAC TOXICITY – chronic congestive cardiomyopathy via. generation of free radicals in myocardial cells - myelosuppression - MUCOSITIS (esp. if continuous infustion) - alopecia - skin necrosis if extravasation - urine discoloration - PULMONARY FIBROSIS - rare hypersensitivity rxn

- reduce cardiac toxicity w/ dexrazoxane or with an iron chelator - can sensitize nml tissue to radiation - increased risk of cardiac fx for pts w/ HTN, preexisting heart dz - resistance via. MDR drug efflux pump - v. minimal myelosuppresion

- cyp450 inhibitor Æ drug interactions

non-Hodgkin’s lymphoma

- limited toxicity - pot’l for infusion related rxns - toxic epidermal necrolysis

breast

- pot’l for infustion related rxns - cardiotoxicity

breast

- hot flashes - increased risk of endometrial carcinoma - venous thrombosis - intraretinal opacities (rare) - thrombocytopenia (rare) - anovulation

- transient bone pain/hypercalcemia indicates that mets will improve - slows normal loss of bone density - lowers LDL - reduces incidence of 2nd

Leuprolide

Flutamide G-CSF

Erythropoietin MISC Leucovorin

Mesna

Dexrazoxane NOT ON TEST Prednisone

- stimulates TGFbeta prodxn GnRH antagonist - reduction of GnRH/LHRH receptors in pituitary Æ fall in testosterone and DHT non-steroidal antiandrogen - blocks cytoplasmic receptors for dihydrotestosterone - activates neutrophils, chemotactic for phagocytes

- synthetic anti-inflammatory corticosteroid w/ lymphocytopenic action - binds intracellular steroid receptor and activates transcription of certain genes; exact mechanism unknown

- hot flashes - loss of libido - impotence

prostate

- hepatic toxicity – monitor pts for elevations in aminotransferase

- produced by activated monocytes, macrophages, activated neutrophils, fibroblasts and endothelial cells

- prophylaxis for chemotherapy associated neutropenia - treatment induced cytopenias anemia assoc w/ renal dz, anemia assoc w/ chemo

- usually administered 24-48 hrs after MTX to prevent rescue of tumor cells - competes with MTX for cell entry

- MTX rescue of normal tissues - w/ 5-FU in tx of colon cancer

- only combines with metabolites in renal tubules

prevention of bladder toxicity of alkylating agent

- hematopoietic growth factor stimulates RBC formation folinic acid - bypasses inhibited enzyme DHFR by supplying reduced folates - increases stability of FdUMP complex to increase activity of 5FU sulfhydral groups bind acrolein (Cyclophosphamide metabolite) or chloracetaldehyde (ifosfamide metabolite) - free radical scavenger

prostate

- to prevent cardiac toxicity of doxorubicin

- ALL, Hodgkin’s and nonHodgkin’s lymphoma

primary breast cancers - prophylaxis for 1-2 wks w/ non-steroidal antiandrogen to block initial flair resonse w/ FSH and LH surges

- recombinant form available