(6) Decreased target: decreased topoisomerase I, 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)
• (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
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 N N CH 3 H N 2 N CONH N NH2 HOOCCH CH2/\--COOH H COOH NH CHb-NH C-NH—CH CH2 H,N 2 Folic acid COOH
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
• 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
o 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)
• 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 )