Parker R J, Vionnet J A, Bostick-Bruton F, Reed E
Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892.
Cancer Res. 1993 Jan 15;53(2):242-7.
The human ovarian cancer cell lines A2780 and A2780/CP70 were studied to investigate the cellular basis for their relative sensitivities to tetrachloro(DL-trans)-1,2-diamminecyclohexaneplatinum(IV) (ormaplatin). Cells were exposed to ormaplatin for 1 h in all experiments. As assessed by colony formation assays, the A2780/CP70 cell line [50% inhibitory dose (IC50) = 3.6 microM] was 9.5-fold more resistant to ormaplatin than the A2780 cell line [IC50 = 0.38 microM]. For cisplatin, the IC50 doses were 40 and 3 microM, respectively. Both cell lines were treated with ormaplatin at doses ranging from 0.10 to 40 microM, for the purpose of studying drug accumulation and efflux, and DNA adduct formation and repair. When these cell lines were treated at their respective IC50 doses, drug accumulation was greater in the resistant cells. When treated at equal microM doses, the sensitive cells formed 8-fold more DNA adduct than the resistant cells. When cells were treated with ormaplatin so as to achieve equivalent levels of platinum-DNA modification, sensitive cells removed 53% of the platinum-DNA damage in the first 6 h after drug exposure, compared to 68% in the resistant cells. We conclude that in human ovarian cancer cells made resistant to cisplatin, there is moderate cross-resistance to ormaplatin. This cross-resistance is not explained by differences in drug accumulation but is associated with reduced platinum-DNA adduct formation, which may be attributable in part to cytosolic inactivation of drug.
对人卵巢癌细胞系A2780和A2780/CP70进行了研究，以探究它们对四氯（DL-反式）-1,2-二胺环己烷铂（IV）（奥马铂）相对敏感性的细胞基础。在所有实验中，细胞均暴露于奥马铂1小时。通过集落形成试验评估，A2780/CP70细胞系[半数抑制剂量（IC50）=3.6微摩尔]对奥马铂的耐药性是A2780细胞系[IC50 = 0.38微摩尔]的9.5倍。对于顺铂，IC50剂量分别为40和3微摩尔。为了研究药物蓄积和外排以及DNA加合物的形成和修复，用0.10至40微摩尔剂量的奥马铂处理这两种细胞系。当以各自的IC50剂量处理这些细胞系时，耐药细胞中的药物蓄积量更大。当以相同的微摩尔剂量处理时，敏感细胞形成的DNA加合物比耐药细胞多8倍。当用奥马铂处理细胞以达到铂-DNA修饰的等效水平时，敏感细胞在药物暴露后的最初6小时内清除了53%的铂-DNA损伤，而耐药细胞为68%。我们得出结论，在对顺铂耐药的人卵巢癌细胞中，对奥马铂存在中度交叉耐药性。这种交叉耐药性不能用药物蓄积的差异来解释，而是与铂-DNA加合物形成减少有关，这可能部分归因于药物的胞质失活。
