Ullman B, Lee M, Martin D W, Santi D V
Proc Natl Acad Sci U S A. 1978 Feb;75(2):980-3. doi: 10.1073/pnas.75.2.980.
Protein in vitro inhibition of thymidylate synthase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) by 5-fluoro-2'-deoxyuridylate requires 5,10-methylenetetrahydrofolate. The cytoxicity 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 requirement 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.
5-氟-2'-脱氧尿苷酸对胸苷酸合酶（5,10-亚甲基四氢叶酸：dUMP C-甲基转移酶，EC 2.1.1.45）的体外蛋白质抑制作用需要5,10-亚甲基四氢叶酸。当细胞内还原型叶酸耗尽时，5-氟-2'-脱氧尿苷对培养的L1210小鼠白血病细胞的细胞毒性会降低，这可以通过限制培养基中的来源或用甲氨蝶呤抑制二氢叶酸还原酶来实现。同样，当细胞缺乏叶酸辅因子时，用5-氟-2'-脱氧尿苷处理的L1210细胞中与胸苷酸合酶共价结合的5-氟-2'-脱氧尿苷酸的细胞内含量会大大减少。L1210细胞最佳生长所需的叶酸低于5-氟-2'-脱氧尿苷最大细胞毒性所需的叶酸。这些发现提供了一种生化原理，可能有助于设计使用5-氟化尿嘧啶类似物的临床方案。
