Methotrexate resistance is due to?

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