Moran R G, Scanlon K L
Department of Biochemistry, University of Southern California, Los Angeles 90033.
Cancer Res. 1991 Sep 1;51(17):4618-23.
Previous studies from this laboratory indicated that the cytotoxic effects of the fluoropyrimidines on mouse leukemic cells are substantially augmented by folinic acid but that these effects are underestimated in growth inhibition experiments. These results have now been extended to two human tumor cell lines, the WiDr colorectal and T-24 bladder carcinoma cells. In both cell lines, the presence of folinic acid in the medium substantially enhanced the cytotoxicity of a 72-h exposure to either 5-fluorouracil (FUra) or 5-fluoro-2'-deoxyuridine. Folinic acid concentration-response curves for enhancement of the cytotoxicity of FUra to WiDr cells were broad but indicated that response was not maximal until at least 10 microM. Likewise, increased length of exposure to 10 microM folinic acid continuously enhanced the cytotoxicity of a 72-h treatment with FUra, but substantial enhancement was observed even after a 2-h exposure to folinate, and there was a diminished increment of cytotoxicity after 24-h exposure to folinic acid. Surprisingly, folinic acid augmentation of the cytotoxicity of a brief exposure to FUra (4 h) was minimal but enhancement of FUra cytotoxicity became much more pronounced with intervals of exposure to FUra of greater than or equal to 24 h. If these results can be mimicked in vivo without undue host toxicity, our experiments suggest that a substantial improvement in the therapeutic activity of FUra plus folinate would result from prolonged exposure to both agents.
该实验室之前的研究表明，甲酰四氢叶酸可显著增强氟嘧啶对小鼠白血病细胞的细胞毒性作用，但在生长抑制实验中这些作用被低估了。现在这些结果已扩展至两种人类肿瘤细胞系，即WiDr结肠癌细胞和T-24膀胱癌细胞。在这两种细胞系中，培养基中存在甲酰四氢叶酸可显著增强72小时暴露于5-氟尿嘧啶（FUra）或5-氟-2'-脱氧尿苷后的细胞毒性。甲酰四氢叶酸增强FUra对WiDr细胞细胞毒性的浓度-反应曲线较宽，但表明至少在10微摩尔时反应才达到最大值。同样，延长暴露于10微摩尔甲酰四氢叶酸的时间可持续增强FUra 72小时处理后的细胞毒性，但即使在暴露于甲酰四氢叶酸2小时后也观察到显著增强，且在暴露于甲酰四氢叶酸24小时后细胞毒性的增量有所减少。令人惊讶的是，短暂暴露于FUra（4小时）时甲酰四氢叶酸对细胞毒性的增强作用最小，但当暴露于FUra的间隔时间大于或等于24小时时，FUra细胞毒性的增强变得更加明显。如果这些结果能在体内得以模拟且不会对宿主产生过度毒性，我们的实验表明，延长两种药物的暴露时间将使FUra加甲酰四氢叶酸的治疗活性得到显著改善。
