Mechanisms determining sensitivity to cisplatin in three mutant Chinese hamster ovary cell lines.

ABSTRACT

To gain insight into factors determining the response of tumours to cisplatin, we studied pathways involved in resistance to cisplatin drug uptake, cytoplasmic detoxification and DNA repair, in three cisplatin-sensitive Chinese hamster ovary (CHO)2 mutant cell lines. The mutant lines, CHO-MMC6, CHO-MMC1, CHO-MMS2, displayed inherent sensitivity to cisplatin (2.2, 4.1 and 10.6-fold, respectively) compared to the CHO-K1 line from which they were derived. CHO-MMS2 was the only mutant to show sensitivity to UV and this was slight (< 2-fold). None of the mutants displayed increased sensitivity to X-irradiation. The CHO-MMS2 cell line appeared to have multiple mechanisms involved in its sensitivity to cisplatin, including increased drug accumulation, decreased levels of glutathione and a decreased capacity for DNA repair. The CHO-MMC1 mutant demonstrated reduced ability for DNA repair in a host cell reactivation assay, but no difference in drug accumulation or glutathione levels compared to the parent. The CHO-MMC6 cell line was not defective in any of the mechanisms studied. These three mutant cell lines demonstrate that similar mechanisms may account for inherent sensitivity or resistance to cisplatin, and suggest that multiple mechanisms may determine the sensitivity of human tumours to cisplatin.