Anomalous relationship between cisplatin sensitivity and the formation and removal of platinum-DNA adducts in two human ovarian carcinoma cell lines in vitro.
Two human ovarian tumor cell lines (SK-OV-3 and TR175), established from patients previously treated with alkylating agents, but not with cisplatin, expressed greater than 23-fold differences in cisplatin sensitivities in vitro. Cisplatin resistance in SK-OV-3 cells appeared to be associated with increased levels of glutathione and activities of glutathione reductase and glutathione peroxidase, with reduced catalase activity. No significant modification of drug uptake was noted and there was only marginally lower (16%) total platination of DNA, measured immunochemically, in these cells compared with the more sensitive TR175 cell line. SK-OV-3 cells, however, showed a significantly lower overall ability to remove drug-induced DNA damage, with an apparent inability to remove either the major DNA-DNA intrastrand cross-links in the sequence pGpG or the adducts cis-Pt(NH3)2d(GMP)2, although by alkaline elution repair of DNA-DNA interstrand cross-links was demonstrated. Significantly more of these interstrand cross-links were induced in these resistant cells. These data provide evidence for the involvement of altered glutathione metabolism and increased tolerance of certain types of drug-induced DNA damage as factors associated with the resistance phenotype of SK-OV-3 cells. Paradoxically, however, although the highly cisplatin-sensitive TR175 cells had lower glutathione levels this was not reflected in significantly higher total platination of DNA, and these cells appeared to be proficient in removing all the major platinum-DNA adducts quantitated in this study. Mechanisms responsible for this relative sensitivity to cisplatin remain to be identified.
Shellard
S A
SA
Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, London, England.
Hosking
L K
LK
Hill
B T
BT
D019328:Buthionine Sulfoximine; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D005978:Glutathione / Q000032:analysis; D005982:Glutathione Transferase / Q000032:analysis; D006801:Humans; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D010984:Platinum / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism
D004273:DNA, Neoplasm; D008717:Methionine Sulfoximine; D010984:Platinum; D019328:Buthionine Sulfoximine; D005982:Glutathione Transferase; D005978:Glutathione; D002945:Cisplatin