Chemotherapy, cancer folate inhibitors

Inhibitors of Folate Metabolism Provide Cancer Chemotherapy Antibacterial Antimalarial Drugs... 

The active form of folate is the tetrahydro-derivative that is formed through reduction by dihydrofolate reductase. This enzymatic reaction (Figure 29.5) is inhibited by trimethoprim, leading to a decrease in the folate coenzymes for purine, pyrimidine, and amino acid synthesis. Bacterial reductase has a much stronger affinity for trimethoprim than does the mammalian enzyme, which accounts for the drug s selective toxicity. [Note Examples of other folate reductase inhibitors include pyrimethamine, which is used with sulfonamides in parasitic infections (see p. 353), and methotrexate, which is used in cancer chemotherapy (see p. 378).]... 

Another characteristic of competitive inhibition is structural similarity between substrate and competitive inhibitor. The similarity allows the inhibitor to bind in the active site of the enzyme. For example, the enzyme dihydrofolate reductase (DHFR) is subject to competitive inhibition by methotrexate and other compounds. Methotrexate is used in cancer chemotherapy because DHFR is required for the synthesis of thymidine triphosphate, a specific precursor of DNA (Fig. 8.8). The normal substrate for DHFR is folate and methotrexate is closely related (Fig. 8.2). 

Competitive enzyme inhibitors are used as drugs. They have structures similar to the natural substrate and can therefore compete with it for access to the same binding site on the enzyme. For example, methotrexate (an anticancer drug) structurally resembles folate, which is the natural substrate for dihydrofolate reductase (Chapter 58). Methotrexate is used to inhibit dihydrofolate reductase in cancer chemotherapy. 

Correct answer = A. Methotrexate interferes with folate metabolism by acting as a competitive inhibitor of the enzyme dihydrofolate reductase. This starves cells for tetrahydrofolate, and makes them unable to synthesize purines and dTMP This is especially toxic to rapidly-growing cancer cells. Overproduction of dihydrofolate reductase, usually caused by amplification of its gene, can overcome the inhibition of the enzyme at the methotrexate concentrations used for chemotherapy, and can result in resistance of the tumor to treatment by this drug. 

Thymidylate synthetase and dihydrofoiate reductase are especially active in tissues with a high rate of cell division, and hence a high rate of DNA replication and a high requirement for thymidylate. Because of this, inhibitors of dihydrofoiate reductase have been exploited as anti-cancer drugs. The most successful of these is methotrexate, an analogue of 10-methyl-tetrahydrofolate. Chemotherapy consists of alternating periods of administration of methotrexate and folate (normally as 5-formyl-tetrahydrofolate, leucovorin) in order to replete the normal tissues and avoid induction of folate deficiency — so-called leucovorin rescue . 

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