Mechanisms of acquired resistance to the orally active platinum-based anticancer drug bis-acetato-ammine-dichloro-cyclohexylamine platinum (i.v.) (JM216) in two human ovarian carcinoma cell lines.

Acquired resistance to the p.o. active lipophilic platinum drug bis-acetato-ammine-dichloro-cyclohexylamine platinum (i.v.) (JM216) was generated in the 41M and CH1 human ovarian carcinoma cell lines, and their resistance mechanisms were compared to parallel cisplatin-resistant (cisR) cell lines. Intracellular platinum accumulation was not reduced in either 41M/JM216R or CH1/JM216R compared to the parent lines after JM216 exposure (1-100 microM for 2 h), and neither 41M/JM216R nor CH1/JM216R was cross-resistant to cadmium chloride, suggesting that metallothionein levels are not elevated. Resistance in 41M/JM216R (resistance factor, 1.9) appeared to be mainly due to elevated glutathione levels; levels were 1.6- and 1.8-fold higher in 41M/JM216R compared to 41M when expressed in terms of protein content and cell number respectively, reflected by a 1.7-fold reduction in total platinum bound to DNA in 41M/JM216R after JM216 exposure (10-100 microM for 2 h). This is in contrast to 41McisR, in which the major resistance mechanism was reduced intracellular accumulation. There was no difference between CH1 and CH1/JM216R in glutathione levels or levels of total platinum bound to DNA and DNA interstrand cross-links immediately after JM216 exposure (10-100 microM for 2 h or 25 microM for 2 h, respectively). In common with CH1cisR, increased DNA repair appeared to be the major resistance mechanism in CH1/JM216R (resistance factor, 6.2). Half times of removal of total platinum from DNA after JM216 exposure (25 microM for 2 h) were 20 h in CH1 and 11 h in CH1JM216R; at 24 h after JM216 exposure (25 microM for 2 h), no removal of DNA interstrand cross-links was observed in CH1, while in CH1/JM216R 20% of cross-links had been removed. These results suggest that compared to cisplatin, acquired resistance to JM216 is less likely to occur through reduced accumulation. However, resistance can result from elevated glutathione levels or increased DNA repair, mechanisms also shown to be involved in cisplatin resistance.