Moran R G, Keyomarsi K
Division of Hematology-Oncology, Childrens Hospital of Los Angeles, CA 90054-0700.
NCI Monogr. 1987(5):159-63.
The fluoropyrimidines, FUra and 5-fluoro-2'-deoxyuridine (FUdR), have been found to be more growth inhibitory and cytotoxic to both mouse and human tumor cells when grown in cell culture medium containing folinic acid. The increment in the activity of these drugs observed in folinate-containing medium was similar for a mouse leukemia cell line and for 4 human leukemia cell lines. This suggests that the mechanism of action of the fluoropyrimidines against these mouse and human cell lines is similar. The most probable mechanism of the interaction between folinic acid and the fluoropyrimidines is stabilization of thymidylate synthase (TS) in inactive complexes with 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and folate cofactor. Such trapping of enzyme in inactive form would negate the effects of the accumulation of the reaction substrate 2'-deoxyuridine-5'-monophosphate. It is suggested that the combination of FUra with folinic acid and, in addition, an inhibitor of ribonucleotide reductase such as hydroxyurea may be more effective than FUra and folinic acid alone.
已发现，当在含有亚叶酸的细胞培养基中培养时，氟嘧啶、氟尿嘧啶（FUra）和5-氟-2'-脱氧尿苷（FUdR）对小鼠和人类肿瘤细胞的生长抑制作用及细胞毒性更强。在含亚叶酸的培养基中观察到的这些药物活性增加，对于一种小鼠白血病细胞系和4种人类白血病细胞系而言是相似的。这表明氟嘧啶对这些小鼠和人类细胞系的作用机制是相似的。亚叶酸与氟嘧啶之间相互作用最可能的机制是使胸苷酸合成酶（TS）与5-氟-2'-脱氧尿苷-5'-单磷酸（FdUMP）和叶酸辅因子形成无活性复合物而得以稳定。酶以无活性形式被捕获会消除反应底物2'-脱氧尿苷-5'-单磷酸积累的影响。有人提出，氟尿嘧啶与亚叶酸联合使用，此外再加上一种核糖核苷酸还原酶抑制剂，如羟基脲，可能比单独使用氟尿嘧啶和亚叶酸更有效。
