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, CH1), 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% compared with vehicle treated control cells (IC50 values) for these cell lines were in the following order: CH1 < 41M < PXN/94 < SKOV-3 < HX/62. None of the cell lines showed saturation of
platinum accumulation (per mg
protein) at 2 h after exposure to
cisplatin concentrations of up to 500 microM. The highest cellular
platinum accumulation was observed in the sensitive 41M cell line which was established from an untreated patient. The lowest accumulation was found in the intrinsically resistant HX/62 cell line. The rate of
platinum accumulation at an equimolar concentration of
cisplatin was 41M > SKOV-3 > CH1 > PXN/94 > HX/62. The relationship between
drug accumulation and cytotoxicity was evaluated by comparing 2-h IC50 values 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 enhanced efflux. Decreased
drug accumulation may also contribute significantly to the lower sensitivity of the PXN/94 cell line to
cisplatin. Interestingly, both the PXN/94 and the sensitive CH1 cell lines, which were established from patients pretreated with
platinum drugs, showed reduced
drug accumulation relative to the 41M cell line. Cellular accumulation of
tetraplatin and JM221 [(
ammine)dibutyratodichloro(cyclohexylamine)platinum(IV)], a novel
platinum(IV) dicarboxylate complex exhibiting enhanced cytotoxicity compared to
cisplatin, was also examined. 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.