Antineoplastic Drugs
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).Alkylating agents: Nitrogen mustards; Cyclophosphamide; Thiotepa. 2-
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
Biological mechanism
Cell cycle: (1)
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.
Cell cycle specific agents (CCSA (3)
Act at specific phase of the cell cycle.
Biochemical Mechanisims:-
Interfere nucleotide synthesis. 1-
Impact the structure and function of DNA- 2
3-Interfere transcription and block RNA synthesis
Interfere protein synthesis and functions. 4-
5-Change hormone lever
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.
Highly cell cycle specific, also "phase specific", e.g., S or M phase
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
1- Broad range. Well established: Acute Lymphoblastic Leukemia of childhood. 2-Choriocarcinoma. (3) Cancers of breast, bladder, and head & neck. (4) Useful in non-Hodgkin's lymphomas
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 Example:-
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.
"Radiomimetic" -- action on DNA resembles radiation. 4-
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 than to liver and kidney, etc. (2) Infertility to both males and females. (3) Mutagenic. (4) Carcinogenic.
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
Adverse effects
1-Bone marrow suppression, most important leukopenia and thrombocytopenia
2-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
1-Vinca Alkaloids
2-Vincristine sulfate and Vinblastine sulfate
Uses
(1) Drug of choice for childhood leukemias in combination with prednisone
(2) Used for lymphoreticular neoplasms, carcinomas, and sarcomas
Antibiotics Antitumor
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)) eaxmpes:-
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
Adverse effects
Three categories of toxicity: a) Local toxicities. b) Acute toxicities. c) Chronic toxicity
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 hydrocortiso
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)