Lewin F, Ringborg U, Skog S, Tribukait B
Department of Medical Radiobiology, Karolinska Institute, Stockholm, Sweden.
Anticancer Drugs. 1995 Jun;6(3):465-70. doi: 10.1097/00001813-199506000-00016.
In earlier studies we showed that a supra-additive cytotoxic effect was obtained with combined treatment with cisplatin and 5-fluorouracil (5-FU) of Bp8 ascites tumor growing in vivo in mice. We therefore studied the DNA interstrand cross-linking after single drug treatment with cisplatin, 5-FU and the drugs combined. The alkaline elution technique was used. 5-FU induced no measurable DNA cross-linking. Cisplatin caused a dose-dependent increase in DNA cross-links 6 h after treatment. When combining cisplatin and 5-FU, no significant change in the number of DNA cross-links was found for this time. The removal of DNA interstrand cross-links was studied after 24 and 36 h. There was no difference in the removal rate between single drug treatment with cisplatin as compared with the combined treatment with the two drugs. Also, the number of DNA single strand breaks (SSB) possibly created when the cisplatin induced cross-links or UV-induced DNA damage were repaired were measured with the alkaline elution technique. No increase in the amount of SSB was seen after combined treatment. Thus, we found no interaction of 5-FU and cisplatin in terms of DNA damage. Other mechanisms for the supra-additive effect found when combining cisplatin and 5-FU have to be considered.
在早期研究中，我们发现顺铂和5-氟尿嘧啶（5-FU）联合治疗可使在小鼠体内生长的Bp8腹水肿瘤产生超相加性细胞毒性作用。因此，我们研究了顺铂、5-FU单药治疗及联合用药后的DNA链间交联情况。采用碱性洗脱技术。5-FU未诱导出可测量的DNA交联。顺铂治疗6小时后导致DNA交联呈剂量依赖性增加。顺铂与5-FU联合使用时，此时DNA交联数量未发现显著变化。在24小时和36小时后研究了DNA链间交联的去除情况。顺铂单药治疗与两种药物联合治疗之间的去除率没有差异。此外，用碱性洗脱技术测量了在修复顺铂诱导的交联或紫外线诱导的DNA损伤时可能产生的DNA单链断裂（SSB）数量。联合治疗后未观察到SSB数量增加。因此，我们发现在DNA损伤方面5-FU和顺铂没有相互作用。必须考虑顺铂与5-FU联合使用时产生超相加性作用的其他机制。
