CISPLATIN SENSITIVITY RESISTANCE IN UV REPAIR-DEFICIENT CHINESE-HAMSTER OVARY CELLS OF COMPLEMENTATION GROUP-1 AND GROUP-3

We assessed the possible role of the human repair genes, ERCC1 and ERC C3, in resistance to cisplatin-induced cytotoxicity. The UV repair-def icient Chinese hamster ovary (CHO) 43:3B [designated ERCC1(-), cell li ne and its paired subline 83-J5, which is stably transfected with the human DNA excision repair gene ERCC1 [designated ERCC1(+)], were used in this study. UV repair-deficient CHO 27-1 cells [designated ERCC3(-) ] and its paired subline designated 'ERCC3(+)', which is stably transf ected with the human DNA excision repair gene ERCC3, were also used. I n each pair of cell lines, we assessed cisplatin cytotoxicity, cellula r drug accumulation and platinum - DNA adduct repair after 1 h drug ex posures. Drug accumulation and DNA repair were assessed by atomic abso rption spectrometry with Zeeman background correction. ERCC1(+) cells (IC50 = 4.0 muM) were 5-fold more resistant to cisplatin than ERCC1(-) cells (IC 50 = 0.75 muM). ERCC1(+) cells repaired 25% of DNA lesions in cellular DNA within a 6 h time period following an IC50 drug exposu re and repaired 48% over 24 h. No DNA repair was observed in ERCC1(-) cells during the same time periods. Both cell lines showed similar pat terns of drug accumulation. For ERCC3(-) cells (IC50 = 54 muM and ERCC 3(+) cells (IC50 = 49 muM), the profiles of cisplatin sensitivity and cellular drug accumulation were similar. When treated with 50 muM cisp latin, these cells showed similar patterns of drug accumulation, and w ere equally efficient at forming and repairing lesions in cellular DNA . These data show that in UV repair-deficient CHO cells, ERCC1 confers resistance to cisplatin and confers the ability to remove platinum fr om cellular DNA. In contrast, ERCC3 does not influence cisplatin drug sensitivity or adduct repair capability. This suggests that ERCC1 may be a determinant of cisplatin resistance, whereas ERCC3 is probably no t.