Mechanism-related circumvention of acquired cis-diamminedichloroplatinum(II) resistance using two pairs of human ovarian carcinoma cell lines by ammine/amine platinum(IV) dicarboxylates.

摘要: Abstract Acquired resistance to cisplatin has been generated in vitro two human ovarian carcinoma cell lines: 41M, established from a previously untreated patient; and CH1, patient treated with cis-diammine-1,1-cyclobutane dicarboxylatoplatinum(II) (carboplatin). In neither line acquired did intracellular detoxification (via increased glutathione or metallothioneins) appear be major determinant of resistance. Resistance 41McisR (resistance factor 4.7) appeared due predominantly reduced platinum accumulation (levels were only 23.8% versus 41M). This was also reflected at the DNA level by similar interstrand cross-links total platinum-DNA adducts measured immediately after 2-h exposure 41M. Conversely, for CH1cisR 6.5), accumulation, initial numbers DNA-interstrand DNA-platinum not significantly different parent CH1 line. is suggestive mechanism involving repair tolerance operating CH1cisR/CH1 pair lines. Cross-resistance carboplatin partial cross-resistance 1,2-diaminocyclohexane-containing agent, (trans-d,l)-1,2-diaminocyclohexane tetrachloroplatinum(IV) (tetraplatin), observed both pairs. However, novel platinum(IV) ammine/amine dicarboxylates, ammine dibutyratodichloro(cyclohexylamine)platinum(IV) (JM221) dibenzoatodichloro(propylamine)platinum(IV) (JM244), completely circumvented produce some collateral sensitivity factors 0.67 0.54, respectively) but showed 3.7 4.6). contrast data cisplatin, levels between 41M lines JM244. These results suggest that which show considerably greater cytotoxicity than are capable circumventing decreased able overcome platination removal.