Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells.
Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells.
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发表时间：
1986-10
期刊：
影响因子：
11.2
通讯作者：
K. Keyomarsi;R. Moran
中科院分区：
文献类型：
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作者：
K. Keyomarsi;R. Moran
在亚叶酸存在下，研究了氟嘧啶对小鼠和人来源的白血病细胞的作用。这种还原的叶酸增强了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。所用的人白血病细胞系（两种T细胞和两种B细胞）仅在比发现对小鼠L1210细胞具有抑制作用的浓度高得多的浓度下受到这些氟嘧啶的影响;然而，在小鼠和人细胞中，在亚叶酸浓度相同的范围内，氟嘧啶的活性增强。而总细胞内叶酸池不断增加的亚叶酸添加到培养基中的每一个增量，氟嘧啶的效力的增强是有限的。FUdR的作用增强超过了5-氟尿嘧啶在人类白血病细胞研究。氟尿嘧啶的细胞毒性（如克隆效率所定义）比生长抑制作用增强到更大的程度，因此注意到令人印象深刻的致死协同作用;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分别导致98或99.9%的细胞杀伤。与以前的预测相反，氟嘧啶对含有叶酸池的小鼠白血病细胞的抑制作用比对叶酸充足的细胞更强，叶酸池对生长不理想。生长速率实验表明，暴露于中等浓度的FUdR的细胞最初受到抑制，但随着时间的推移恢复，而在细胞暴露于FUdR和亚叶酸，最初的生长抑制作用持续。我们的结论是，亚叶酸稳定的氟嘧啶对小鼠和人白血病细胞群体的胸苷酸合成酶的影响，这种增强反映在抑制这些细胞的生长和致死性。我们认为，只有剂量的氟嘧啶，最初能够抑制胸苷酸合成酶的高度将与过量的还原叶酸协同。
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.