Two antineoplastic drugs are shown to inhibit intracellular thymidylate formation. The chemotherapeutic effect of drug X can be overcome by N⁵-formyl-tetrahydrofolate supplementation, but that of drug Y is not affected. The drugs described in this scenario are most likely which of the following?

Question

Two antineoplastic drugs are shown to inhibit intracellular thymidylate formation. The chemotherapeutic effect of drug X can be overcome by N⁵-formyl-tetrahydrofolate supplementation, but that of drug Y is not affected. The drugs described in this scenario are most likely which of the following?
Two antineoplastic drugs are shown to inhibit intracellular thymidylate formation. The chemotherapeutic effect of drug X can be overcome by N<sup>5</sup>-formyl-tetrahydrofolate supplementation, but that of drug Y is not affected. The drugs described in this scenario are most likely which of the following? A) A B) B C) C D) D E) E

Quizplus · Accepted Answer

11ec160b_3bdf_b277_9249_4d48bc218ce3_MD0001_00 The two antineoplastic agents described in the question stem are methotrexate (Drug X) and 5-fluorouracil (Drug Y). Methotrexate is a folic acid analog that functions by binding and inactivating dihydrofolate reductase, the enzyme responsible for reducing folic acid to tetrahydrofolate. Tetrahydrofolate participates in the transfer of carbon groups in certain intracellular reactions including purine and thymidine synthesis. 5-fluorouracil (5-FU) is a pyrimidine analog that primarily functions to inhibit DNA synthesis by inhibition of thymidylate synthetase after enzymatic conversion to its nucleotide floxuridine monophosphate by any of a number of intracellular reactions. The key metabolic difference between methotrexate and 5-fluorouracil is that methotrexate prevents the reduction of folic acid to tetrahydrofolate, while 5-FU binds tetrahydrofolate and thymidylate synthetase in a stable-reaction intermediate form, thereby effectively decreasing the amount of thymidylate synthetase available for thymidine synthesis. Leucovorin (N⁵-formyl-tetrahydrofolate) is a tetrahydrofolate derivative that does not require reduction by dihydrofolate reductase before it can function as a cofactor for thymidylate synthase and other enzymes involved with purine and amino acid synthesis. Because leucovorin bypasses the dihydrofolate reductase step that is inhibited by methotrexate, it can be used to "rescue" normal cells from the toxicity of methotrexate. 5-FU, on the other hand, requires the presence of reduced folate in order to form complexes with thymidylate synthetase. 5-FU has a reduced cytotoxic effect in cells that are deficient in tetrahydrofolate. For this reason, leucovorin can be utilized to potentiate the toxicity of fluoropyrimidines such as fluorouracil by strengthening the association of the drug with thymidylate synthase. (Choice A) Cytarabine, like 5-FU, is also a pyrimidine analog antimetabolite that is incorporated into DNA leading to strand termination. It does not affect folate metabolism. Gemcitabine is another pyrimidine analog that functions much like cytarabine. It differs from cytarabine in that it is not S-phase specific, likely owing to additional cytotoxic functions such as inhibition of ribonucleotide reductase. (Choice C) Fludarabine is a deamination-resistant purine nucleotide analog that exerts its cytotoxicity by many mechanisms, including inhibition of DNA polymerase, DNA primase, DNA ligase, and ribonucleotide reductase. Fludarabine is used to treat chronic lymphocytic leukemia (CLL). Educational Objective: Methotrexate and 5-FU both effectively inhibit thymidylate formation, but the chemotherapeutic effect of methotrexate is overcome by N⁵-formyl-tetrahydrofolate (folinic acid, leucovorin) supplementation.

Two Antineoplastic Drugs Are Shown to Inhibit Intracellular Thymidylate Formation