Comparison of Cellular Accumulation and Cytotoxicity of Cisplatin with That of Tetraplatin and Amminedibutyratodichloro(cyclohexylamine)platinum(IV) (JM221) in Human Ovarian Carcinoma Cell Lines1

We have compared the cellular accumulation and Cytotoxicity of three platinum compounds in a panel of five human ovarian carcinoma cell lines. The cell lines, which were established from both untreated and pretreated patients, showed a wide range in sensitivity to cisplatin and other platinum drugs. The panel consisted of two sensitive (41M, CHI), one in vivo acquired resistant (PXN/94) with moderate sensitivity, and two intrinsically resistant (SKOV-3, HX/62) cell lines. The cisplatin 2-h concentration of drug required to inhibit cell growth by 50% com pared with vehicle treated control cells (IC50 values) for these cell lines were in the following order: CHI < 41M < PXN/94 < SKOV-3 < HX/62. None of the cell lines showed saturation of platinum accumu lation (per mg protein) at 2 h after exposure to cisplatin concentrations of up to 500 /MI. The highest cellular platinum accumulation was ob served in the sensitive 41M cell line which was established from an untreated patient. The lowest accumulation was found in the intrinsi cally resistant HX/62 cell line. The rate of platinum accumulation at an equimolar concentration of cisplatin was 41M > SKOV-3 > CHI > PXN/94 > HX/62. The relationship between drug accumulation and Cytotoxicity was evaluated by comparing 2-h IC5Uvalues with platinum accumulation following exposure to both equimolar and equitoxic doses of the agent. The results suggest that reduced drug accumulation may play a partial role in the mechanism of intrinsic resistance to cisplatin in one cell line (SKOV-3) and a major role in another (HX/62), where reduced accumulation is attributable to reduced uptake rather than en hanced efflux. Decreased drug accumulation may also contribute signif icantly to the lower sensitivity of the PXN/94 cell line to cisplatin. Interestingly, both the PXN/94 and the sensitive CHI cell lines, which were established from patients pretreated with platinum drugs, showed reduced drug accumulation relative to the 41M cell line. Cellular accu mulation of tetraplatin and JM221 [(ammine)dibutyratodichloro(cyclohexylamine)platinum(IV)], a novel platinum(IV) dicarboxylate complex exhibiting enhanced Cytotoxicity compared to cisplatin, was also exam ined. Comparison with platinum accumulation from cisplatin suggests that the increased Cytotoxicity of tetraplatin and JM221 may be related to their increased accumulation. Significantly both agents are more lipophilic than cisplatin, which may account partially for their improved uptake in cisplatin resistant cells.