Inhibitors of thymidine synthesis can be used as anticancer drugs because they block DNA synthesis and decrease rates of cell division. One of the anticancer drugs that inhibits thymidine synthesis is methotrexate, which targets the enzyme dihydrofolate reductase. This enzyme is required to generate the thymidylate synthase substrate methylenetetrahydrofolate, a coenzyme required in the pathway to generate the nucleotide base thymine. By inhibiting dihydrofolate reductase activity and the production of methylenetetrahydrofolate, rapidly dividing cells cannot synthesize DNA quickly enough because they run out of the required nucleoside thymidine. Unfortunately, cancer cells treated with methotrexate often acquire mutations in the enzyme dihydrofolate reductase, which block methotrexate binding without significantly altering enzymatic activity. Once cancer cells become resistant to methotrexate, they are able to rapidly proliferate causing cancer progression and recurrence of disease symptoms.
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