Mechanisms of drug resistance to the platinum complex ZD0473 in ovarian cancer cell lines

Acquired drug resistance to the sterically hindered platinum drug ZD0473 (f ormerly known as JM473 and AMD473) and currently being tested in phase I cl inical trials, has been studied in two human ovarian carcinoma cell lines ( CHI and A2780) where previously, acquired cisplatin resistance has been des cribed. Common mechanisms of resistance were observed in A2780 acquired cis platin and ZD0473R (resistant) lines (including reduced drug transport and DNA platination, increased glutathione (GSH) and loss of the MLH1 DNA misma tch repair gene). However, contrasting mechanisms were observed in the CH1 sublines. While ZD0473 retained activity against the acquired cisplatin res istant sublines, cisplatin did not circumvent acquired ZD0473 resistance, T he trans platinum complex JM335 circumvented resistance in CH1cisR and A278 0ZD0473R lines, but not in A2780cisR or CH1ZD0473R cells, Overexpression of metallothionein (MT) in A2780 cells by stable gene transfection resulted i n protection from the growth-inhibitory effects of cadmium chloride (3.8-fo ld) and a range in protection with platinum drugs (from 7-fold with cisplat in, but only 1.3-fold with ZD0473). Overall, the results show that some mec hanisms of resistance to ZD0473 are shared with those previously described in the same parental lines for cisplatin (e.g. in A2780), but in the CH1 li nes, differing mechanisms were apparent. Moreover, ZD0473 possesses distinc t cellular pharmacological properties in comparison with cisplatin with res pect to reduced interactions with MTs, a thiol-containing species associate d with tumour resistance to cisplatin. (C) 2000 Elsevier Science Ltd. All r ights reserved.