This is a real-world medical entrance exam question, please give the true answer based on the question and selection. Topic name: Anti-Neoplastic Agents, Subject name: Pharmacology
[{'content': 'Methotrexate resistance is due to? \nSelect and explain. \nA. Increased concentrations of intracellular DHFR through gene amplification, B. Failure of efflux pumps, C. Bacterial modification, D. Increased synthesis of poly glutamates', 'role': 'user'}, {'content': 'Answer: A \nExplanation: ANSWER: (A) Increased concentrations of intracellular DHFR through gene amplificationREF: Goodman and Gillman s 11TH edition, page 871, Lehninger biochemistry, 4th edition, page 877"Protein that confers the ability to withstand methotrexate is an inhibitor of dehydrofolate reductase (DHFR). Methotrexate resistance occurs usually as a result of mutation or amplification of the DHFR gene"During thymidylate synthesis, N5, N10- methylene tetrahydrofolate is converted to 7, 8-dihydrofolate. This cycle is a major target of several chemo therapeutic agents (5FU & methotrexate). In cells, fluorouracil is converted to FdUMP, which inhibits thymidylate synthase. Methotrexate (structural analogue of tetrahydrofolate) inhibits dihydrofolate reductase by competitive inhibitionRemember: structural analogue and agonist are two different things: Methotrexate is structural analogue of H4 Folate still it antagonises Folate by reducing dihydrofolate conversion to H4 Folate by competitive inhibition of dihydrofolate reductaseAlso know:AM1NOPTERIN is another Folate analogue, identical to methotrexate except that it lacks a methyl group.TRIMETHOPRIM is another inhibitor of bacterial dihydrofolate reductase that was developed as an antibiotic.PROGUANIL is an antimalarial drug, which is a folate antagonist', 'role': 'assistant'}]