Keyomarsi K, Moran R G
Cancer Res. 1986 Oct;46(10):5229-35.
The effects of the fluoropyrimidines on leukemic cells of mouse and human origin have been studied in the presence of folinic acid. This reduced folate enhanced the cytotoxicity and the growth inhibitory potency of 5-fluorouracil (5-FUra) and of 5-fluoro-2'-deoxyuridine (FUdR) against all cell lines examined. The human leukemic cell lines used (two T- and two B-cells) were affected by these fluoropyrimidines only at substantially higher concentrations than were found to be inhibitory to mouse L1210 cells; however, the enhancement of the activity of the fluoropyrimidines occurred over the same range of folinic acid concentrations in mouse and human cells. Whereas the total intracellular folate pool increased continuously with every increment of folinic acid added to the medium, the enhancement of the potency of the fluoropyrimidines was limited. Augmentation of the effects of FUdR exceeded that of 5-fluorouracil in the human leukemic cells studied. The cytotoxicity of the fluoropyrimidines (as defined by cloning efficiency) was enhanced to a greater extent than was growth inhibition so that an impressive lethal synergism was noted; for instance, exposure of L1210 cells to nontoxic concentrations of 5-fluorouracil or FUdR in the presence of folinic acid resulted in a 98 or 99.9% cell kill, respectively. In contrast to previous predictions, the fluoropyrimidines were more inhibitory to mouse leukemic cells containing folate pools that were suboptimal for growth than for folate-replete cells. Growth rate experiments showed that cells exposed to moderate concentrations of FUdR were initially inhibited but recovered with time, whereas in cells exposed to both FUdR and folinic acid, the initial growth inhibitory effects were sustained. We conclude that folinic acid stabilizes the effects of the fluoropyrimidines on thymidylate synthase of both mouse and human leukemic cell populations and that this enhancement is reflected in both inhibition of the growth of and the lethality to these cells. We suggest that only doses of the fluoropyrimidines that are capable of initially inhibiting thymidylate synthase to a high degree will be synergistic with excess reduced folates.
在亚叶酸存在的情况下，研究了氟嘧啶对源自小鼠和人类的白血病细胞的影响。这种还原型叶酸增强了5-氟尿嘧啶（5-FUra）和5-氟-2'-脱氧尿苷（FUdR）对所有检测细胞系的细胞毒性和生长抑制效力。所使用的人类白血病细胞系（两种T细胞系和两种B细胞系）仅在浓度远高于对小鼠L1210细胞具有抑制作用的浓度时，才会受到这些氟嘧啶的影响；然而，在小鼠和人类细胞中，氟嘧啶活性的增强发生在相同范围的亚叶酸浓度下。虽然随着向培养基中添加的亚叶酸每次增加，细胞内总叶酸池持续增加，但氟嘧啶效力的增强是有限的。在所研究的人类白血病细胞中，FUdR作用的增强超过了5-氟尿嘧啶。氟嘧啶的细胞毒性（以克隆效率定义）比生长抑制增强的程度更大，因此观察到显著的致死协同作用；例如，在亚叶酸存在下，将L1210细胞暴露于无毒浓度的5-氟尿嘧啶或FUdR中，分别导致98%或99.9%的细胞死亡。与先前的预测相反，氟嘧啶对叶酸池低于生长最佳水平的小鼠白血病细胞的抑制作用比对叶酸充足的细胞更强。生长速率实验表明，暴露于中等浓度FUdR的细胞最初受到抑制，但随时间恢复，而在同时暴露于FUdR和亚叶酸的细胞中，最初的生长抑制作用持续存在。我们得出结论，亚叶酸稳定了氟嘧啶对小鼠和人类白血病细胞群体胸苷酸合成酶的作用，并且这种增强反映在对这些细胞生长的抑制和致死性上。我们建议，只有能够最初高度抑制胸苷酸合成酶的氟嘧啶剂量才会与过量的还原型叶酸产生协同作用。
