Potent in vitro inhibition of thymidylate synthetase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 184.108.40.206) by 5-fluoro-2'-deoxyuridylate requires 5,10-methylenetetrahydrofolate. The cytotoxicity of 5-fluoro-2'-deoxyuridine towards cultured L1210 mouse leukemia cells is reduced when intracellular reduced folates are depleted, either by limiting the source in media or by inhibition of dihydrofolate reductase with methotrexate. Likewise, the intracellular amount of 5-fluoro-2'-deoxyuridylate covalently bound to thymidylate synthase in L1210 cells treated with 5-fluoro-2'-deoxyuridine is greatly diminished when cells are depleted of folate cofactors. The folate requirements for optimal growth of L1210 cells is lower than that required for maximal cytotoxicity of 5-fluoro-2'-deoxyuridine. These findings provide a biochemical rationale that may be useful in designing clinical protocols that use 5-fluorinated uracil analogs.
|Number of pages
|Proceedings of the National Academy of Sciences of the United States of America
|Published - 1978
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