Characterization of a cis-Diamminedichloroplatinum(II)-resistant Human Ovarian Cancer Cell Line and Its Use in Evaluation of Platinum Analogues

Abstract

Human ovarian cancer cell lines with stable cisplatin resistance have been developed by chronic exposure of the parent cisplatin-sensitive A2780 line to increasing concentrations of cisplatin. 2780^CP8 (CP8 refers to this cell line's growth in medium containing 8 µm cisplatin) has several clonal cytogenetic abnormalities but lacks homogeneously staining regions or double-minute chromosomes. It has a significantly greater monolayer growth rate, cloning efficiency in agarose, and total glutathione content compared to the A2780 line, but similar activities of several glutathione-dependent enzymes. The 2780^CP8 subline is 7.3-fold resistant to cisplatin compared to the A2780 line, as well as cross-resistant to irradiation and melphalan. It is not cross-resistant to Adriamycin, but this develops with increased cisplatin resistance (14-fold) obtained by further cisplatin exposure of 2780^CP8. Of the cisplatin analogues tested which are of current clinical interest, carboplatin, iproplatin, and tetraplatin, only the latter is more cytotoxic than cisplatin in the A2780 and 2780^CP8 lines. The 2780^CP8 subline is also cross-resistant to these analogues in the relative order carboplatin > iproplatin > tetraplatin (most to least cross-resistant). Treatment of a highly cisplatin resistant cell line (2780^CP8) with either melphalan or cisplatin was associated with a significant increase in [³H]thymidine incorporation into DNA in the presence of 10 mm hydroxyurea compared with the parent sensitive cell line which showed essentially no capacity to repair DNA damage by these drugs. A2780 and its cisplatin-resistant cell lines may thus be useful in studying drug resistance mechanisms, in screening new drugs for activity (especially against drug resistant tumors), and in formulating induction and salvage therapies for ovarian cancer.