Mechanism-related Circumvention of Acquired cis-Diamminedichloroplatinum(II) Resistance Using Two Pairs of Human Ovarian Carcinoma Cell Lines by Ammine/ Amine Platinum(IV) Dicarboxylates1

Acquired resistance to cisplatin has been generated in vitro in two human ovarian carcinoma cell lines: 41M, established from a previously untreated patient; and CHI, from a patient previously treated with cisplatin and cis-diammine-l,l-cyclobutane dicarboxylatoplatinum(II) (carboplatin). In neither cell line with acquired resistance did intracellular detoxification (via increased glutathione or metallothioneins) ap pear to be a major determinant of resistance. Resistance in 41McisR (resistance factor of 4.7) appeared to be due predominantly to a reduced platinum accumulation (levels were only 23.8% in 41McisR versus 41M). This was also reflected at the DNA level by a similar level of reduced DNA interstrand cross-links and total platinum-DNA adducts measured immediately after a 2-h exposure to cisplatin in 41McisR versus 41M. Conversely, for CHlcisR (resistance factor of 6.5), plati num accumulation, and initial numbers of DNA-interstrand cross-links and total DNA-platinum adducts were not significantly different from the parent CHI line. This is suggestive of a resistance mechanism involving increased DNA repair or tolerance to platinum-DNA adducts operating in the CHlcisR/CHl pair of lines. Cross-resistance to car boplatin and partial cross-resistance to the 1,2-diaminocyclohexane-containing agent, (rrans-</,/)-l,2-diaminocyclohexane tetrachloroplatinum(IV) (tetraplatin), was observed in both pairs. However, two novel platinum!IV) ammine/amine dicarboxylates, ammine dibutyratodichloro(cyclohexylamine)platinum(IV) (JM221) and ammine dibenzoatodichloro(propylamine)platinum(IV) (JM244), completely circum vented resistance in 41McisR to produce some collateral sensitivity (resistance factors of 0.67 and 0.54, respectively) but showed crossresistance in CHlcisR (resistance factors of 3.7 and 4.6). In contrast to the data for cisplatin, intracellular platinum levels were not significantly different between the 41M and 41McisR pair of cell lines after exposure to JM244. These results suggest that the ammine/amine platinum(IV) dicarboxylates, which show considerably greater in vitro cytotoxicity than cisplatin, are capable of circumventing acquired cisplatin resis tance which is due to decreased intracellular accumulation but are not able to overcome resistance at the level of DNA platination and removal.