Chapter 49 Antineoplastic Drugs Department of pharmacology Liu

Chapter 49 Antineoplastic Drugs Department of pharmacology Liu xiaokang(刘小康） 2010, 3

Categories: • 1) Antimetabolites: a) Folic Acid Analogs (Methotrexate, MTX). b) Pyrimidine analogs (Fluorouracil, 5 -FU; Fluorodeoxyuridine; Cytarabine). d) Purine analogs (6 Mercaptopurine, 6 -MP; 6 -Thioguanine, 6 -TG). • 2) Alkylating agents: Nitrogen mustards; Cyclophosphamide; Thiotepa. • 3) Natural products: Vinca alkaloids (Vincristine; Vinblastine; Vinorelbine); Paclitaxel (Taxol® )

• 4) Antiumor antibiotics: Anthracyclines (Doxorubicin hydrochloride, Daunorubicin, Bleomycin) • 5) Miscellaneous agents: Cisplatin; Carboplatin; Asparaginase; Hydroxyurea; Corticosteroid

Mechanisms: • Biological mechanism: • (1) Cell cycle: • a) Gap 1 (G 1 phase). b) DNA synthesis (S phase). c) Gap 2 (G 2 phase). d) Mitosis (M phase). G 0 is a resting phase in which the cells are not prolifering.

• (2) Cell cycle nonspecific agents (CCNSA): • Kill proliferating cells preferentially, act on cells at all phases. • (3) Cell cycle specific agents (CCSA): • Act at specific phase of the cell cycle.

• Biochemic mechanism: • 1) Interfere nucleotide synthesis. • 2) Impact the structure and function of DNA • 3) Interfere transcription and block RNA synthesis. • 4) Interfere protein synthesis and functions. • 5) Change hormone lever.

Resistance mechanism • (1) Defective activation: Cyclophosphamide requires metabolic activation, Methotrexate conversion to more active MTXpolyglutamate in cells

• (2) Increased inactivation: e. g. , aldehyde dehydrogenase converse cyclophosphamide to inactive metabolite. • (3) Altered nucleotide pools: Can occur with antimetabolites.

• (4) Altered DNA repair: Repair mechanisms increased, i. e. , ability to remove cross-links, Affect the action of bleomycin and other DNA-directed drugs • (5) Altered target: Less affinity for drug, Methotrexate (Dihydrofolate reductase changes ).

• (6) Decreased target: decreased topoisomerase II, e. g. , etoposide • (7) Gene amplification: Methotrexate (MTX) increase dihydrofolate reductase, hence Requires more MTX to block • (8) Decreased accumulation: Decreased uptake (Methotrexate -- carrier protein decreases). Increased Efflux (Multidrug Resistance, P-Glycoprotein (g. P-170) in membrane, pumps drug out)

Commonly used antineoplastic drugs • Antimetabolites • Group Characteristics: • (1) Resemble NORMAL substrates. • (2) Most inhibit DNA synthesis. • (3) Some inhibit RNA synthesis and/or function. (4) Bone Marrow cell replication is profoundly inhibited. • (5) GI toxicity great with some drugs. • (6) Highly cell cycle specific, also "phase specific", e. g. , S or M phase

Methotrexate (MTX) • Structure:

• Mechanism of action: • (1) Folic Acid Analogue, Carrier transport into cell. (2) Binds strongly to DHFR to deplete THF, Decreases 1 carbon transfers in Purine synthesis, Decreases [1 -C-THF] intracellular which decreases d. UMP d. TMP, Therefore, decreases NUCLEIC ACID synthesis.

• Adverse effects: • (1) Dose limiting: a) Myelosuppression (Thrombocytopenia and Leukopenia, Nadirs 7 -10 days after Rx, Recovery 1421 days). b) GI toxicity (Oral mucositis is early sign of GI toxicity, Severe mucositis, Small bowel ulceration & bleeding, Diarrhea -- requires cessation to prevent perforation of gut )

• (2) Nephrotoxicity: Conventional doses, infrequent toxicity; High doses, toxicity can be severe • (3) Immunosuppression. • (4) Hepatotoxicity.

• Clinical Uses: • Broad range. Well established: (1) Acute Lymphoblastic Leukemia of childhood. (2) Choriocarcinoma. (3) Cancers of breast, bladder, and head & neck. (4) Useful in non-Hodgkin's lymphomas

Flurouracil (5 -FU) • Structure:

• Mechanism of action: • (1) Activated by conversion to nucleotide • (2) Inhibits DNA synthesis: Inhibition of Thymidylate synthase—the most important mechanism of action (MOA) in rapidly growing tumors (? ) • (3) 5 -FU Incorporated into RNA: Interfere with RNA processing - All types, May be most important MOA in slowly growing tumors.

• Adverse effects: • (1) Dose limiting: a) Bone marrow -- esp. with bolus administration. Leukopenia & Thrombocytopenia (nadir 9 -14 days after 5 days of Rx, recovery by day 21). b) GI Toxicity -- esp. with infusion administration. usually Stomatitis & Diarrhea 4 -7 days after Rx.

• (2) Effect of route and schedule on adverse effects: • IV bolus: myelosuppression is dominant; Prolonged Rx, may cause megaloblastic anemia • Continuous IV Infusion: Frequently produce, stomatitis, nausea, vomiting, and diarrhea; Hepatotoxicity (elevated transaminases); myelosuppression less common

• (3) Effect of peak 5 -FU concentration: • Acute, reversible cerebellar syndrome: somnolence, ataxia of trunk or extremities, unsteady gait, slurred speech, nystagmus

• (4) Other adverse effects: • Hyperpigmentation of skin is frequent and may be accompanied by photosensitivity; Toxic effect of radiation to skin may be enhanced; Alopecia, acute and chronic conjunctivitis, and nail changes may be observed.

• Clinical Use of 5 -FU: • (1) Single agent: Palliative in advanced colorectal carcinoma • (2) Combination: Breast cancer; Carcinomas of ovary, stomach, pancreas • (3) Sequential MTX + 5 -FU: Head and neck cancer

Alkylating Agents • Nitrogen mustard • General view: • (1) Developed from mustard war gases of Word War I which were highly reactive vesicants. • (2) First chemicals used for cancer Rx. • (3) Not cell cycle specific, but still more active in dividing tissues. • (4)"Radiomimetic" -- action on DNA resembles radiation.

• Mechanism of action: • (1) Highly reactive: Form covalent bonds with NDA, RNA and protein • (2) Consequences: a) DNA-DNA strand DNA-Protein cross-links. b) Misreading of genetic code. c) DNA Chain breaks

• Adverse effects of alkylating agents: • (1) More toxic to bone marrow and gut than to liver and kidney, etc. (2) Infertility to both males and females. (3) Mutagenic. (4) Carcinogenic. • Tumor resistance: • Develops slowly & may require several genetic / biochemical changes

• Clinical Uses: • Wide spectrum; Lymphoreticular tissue tumors; Limited activity against sarcomas.

Cyclosphamide

• Mechanism of action: • Hepatic cytochrome P-450 system, enzymes phosphatase and phosphamidase are primary activators (hydrolyze P-N bond) to intermediate, aldophosphamide, which nonenzymatically breaks down to -Phosphoramide mustard (bifunctional) & Acrolein

• Pharmacokinetics: • Oral bioavailability = 90 -100%, IV injection no local irritation • Half-life -- cyclophosphamide -- 3 -10 h; aldophosphamide -1. 6 h; phosphoramide mustard -- 8. 7 h. • Most metabolized-- < 14% unchanged in urine.

• Clinical Applications: • (1) Most widely used alkylating agent, in part due to availability of oral route • (2) Active on lymphoproliferative diseases, e. g. , Hodgkin's disease and Chronic lymphocytic leukemia

• (3) Significant activity vs multiple myeloma & ovarian, breast, small cell lung carcinoma • (4) Many combinations.

• Adverse effects: • (1) Bone marrow suppression, most important leukopenia and thrombocytopenia • (1) Nausea and vomiting said to be rare • (3) Sterile necrotizing hemorrhagic cystitis. Acrolein is probable cause. To minimize cyctitis--high water intake and take in AM

Natural Products • Vinca Alkaloids • Vincristine sulfate and Vinblastine sulfate

• Mechanism of action: • (1) Uptake by energy dependent carrier • (2) Bind to tubulin in microtubules to cause their dissolution. Contrast to Taxol which stabilizes tubules. • (3) No cross resistance between vincristine and vinblastine

• Uses: • (1) Drug of choice for childhood leukemias in combination with prednisone • (2) Used for lymphoreticular neoplasms, carcinomas, and sarcomas

• Adverse effects: • (1) Severe vesicant. Must be careful of IV equipment to avoid slough. • (2) Neurotoxicity: a) Mild sensory neuropathy with sensory impairment and paresthesia--Keep Rx. b) Severe paresthesias, loss of reflexes, ataxia, and muscle wasting-- stop Rx. c) Constipation and abdominal pain - take laxatives. e) Less hematologic effects than many other cytotoxic drugs.

Antitumor Antibiotics • General characteristics: • (1) All interact with DNA and/or RNA, but may also interact with other cellular substituents. • (2) Schedule dependence: LESS "phasespecific" than antimetabolites. • (3) Tissue necrosis is only generalizable toxicity. • (4)All IV except bleomycin

• Doxorubicin(Adriamycin. R) • Mechanism of action: • (1) DNA topoisomerase II inhibitor: Crucial to DNA replication and transcription. • (2) Traditional explanations of MOA: a) intercalates between base pairs of DNA and inhibits DNA-dependent RNA synthesis. b) Generates free radicals that cause membrane damage and DNA strand breaks.

• Resistance: • (1) Alterations in Topoisomerase II activity. • (2) Increased inactivation of radicals: a) Increase in glutathione-dependent enzymes, e. g. , glutathione-peroxidase. b) Altered NADPH contents. • (3) Increase drug efflux: a) Multi-drug resistance (MDR). b) P-glycoprotein (g. P 170) pump is product of mdr gene

• Adverse effects: • Three categories of toxicity: a) Local toxicities. b) Acute toxicities. c) Chronic toxicity • (1) Local Toxicity -- Extravasation • Extravasation -- DON'T! Severe local tissue necrosis to point of damaging underlying structures; If occurs, treat immediately: Remove blood from IV line; Apply ice, steroid cream; Locally adm. sodium bicarbonate and hydrocortisone.

• (2) Local Toxicity -- Radiation Recall • Interaction of doxorubicin and radiation in some tissues to produce enhanced reactions. • Reactions include: a) Skin: ulceration and necrosis. b) Pulmonary: fibrosis and sloughing of esophageal mucosa. c) Heart, and intestinal mucosa may also be affected

• (3) Acute Toxicities • a) Hematologic: Leukopenia with nadir 710 days; recovery typically by 21 days; Thrombocytopenia and anemia less common • b) If give too fast: "Histamine-release" syndrome; Cardiac arrest preceded by ECG changes

• (4) Chronic Toxicities • a) Cardiomyopathy and congestive heart failure: require cessation of Rx after cumulative dose of 550 to 600 mg/m 2; must maintain record of total dose.

• Clinical Indications: • (1) Broad spectrum anti-cancer activity. • (2) Hodgkin's disease, non-Hodgkin's lymphomas, sarcomas, acute leukemia, and breast, lung, and ovarian carcinomas all responsive • (3) Activity observed in bladder tumors, and carcinomas of prostate, thyroid, endometrium, head and neck, and other solid tumors • (The end)