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 (G1 phase). b) DNA synthesis (S

phase). c) Gap 2 (G2 phase). d) Mitosis

(M phase). G0 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 DN

A• 3) Interfere transcription and block RNA s

ynthesis.• 4) Interfere protein synthesis and functions.• 5) Change hormone lever.

Resistance mechanism

• (1) Defective activation: Cyclophosphamide requires metabolic activation, Methotrexate conversion to more active MTX-polyglutamate 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 (gP-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 dUMP dTMP, Therefore, decreases NUCLEIC ACID synthesis.

• Adverse effects:• (1) Dose limiting: a) Myelosuppression

(Thrombocytopenia and Leukopenia, Nadirs 7-10 days after Rx, Recovery 14-21 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 and 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 th

an to liver and kidney, etc. (2) Infertility to both males and females. (3) Mutagenic. (4) Carcinogenic.

• Tumor resistance: • Develops slowly & may require several ge

netic / biochemical changes

• Clinical Uses:

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

Cyclosphosphamide

• Mechanism of action:• Hepatic cytochrome P-450 system, enzymes pho

sphatase 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 inject

ion no local irritation • Half-life -- cyclophosphamide -- 3-10 h; al

dophosphamide -- 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 impo

rtant leukopenia and thrombocytopenia • (1) Nausea and vomiting said to be rare • (3) Sterile necrotizing hemorrhagic cystiti

s. Acrolein is probable cause. To minimize cyctitis--high water intake and take in AM

Natural Products

• Vinca Alkaloids• Vincristine sulfate and Vinblastine sulfat

e

• 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 neurop

athy 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 "phase-specific" than antimetabolites.

• (3) Tissue necrosis is only generalizable toxicity.

• (4)All IV except bleomycin

• Doxorubicin(AdriamycinR)• Mechanism of action: • (1) DNA topoisomerase II inhibitor: Cruc

ial to DNA replication and transcription. • (2) Traditional explanations of MOA: a) i

ntercalates 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 activi

ty. • (2) Increased inactivation of radicals: a) I

ncrease in glutathione-dependent enzymes, e.g., glutathione-peroxidase. b) Altered NADPH contents.

• (3) Increase drug efflux: a) Multi-drug resistance (MDR). b) P-glycoprotein (gP-170) pump is product of mdr gene

• Adverse effects: • Three categories of toxicity: a) Local toxi

cities. b) Acute toxicities. c) Chronic toxicity

• (1) Local Toxicity -- Extravasation • Extravasation -- DON'T! Severe local tiss

ue 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

7-10 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/m2; must maintain record of total dose.

• Clinical Indications: • (1) Broad spectrum anti-cancer activity. • (2) Hodgkin's disease, non-Hodgkin's lym

phomas, 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)