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.