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

Acquired drug resistance to the sterically hindered platinum drug ZD0473 (formerly known as JM473 and AMD473) and currently being tested in phase I clinical trials, has been studied in two human ovarian carcinoma cell lines (CH1 and A2780) where previously, acquired cisplatin resistance has been described. Common mechanisms of resistance were observed in A2780 acquired cisplatin and ZD0473R (resistant) lines (including reduced drug transport and DNA platination, increased glutathione (GSH) and loss of the MLH1 DNA mismatch repair gene). However, contrasting mechanisms were observed in the CH1 sublines. While ZD0473 retained activity against the acquired cisplatin resistant sublines, cisplatin did not circumvent acquired ZD0473 resistance. The trans platinum complex JM335 circumvented resistance in CH1cisR and A2780ZD0473R lines, but not in A2780cisR or CH1ZD0473R cells. Overexpression of metallothionein (MT) in A2780 cells by stable gene transfection resulted in protection from the growth-inhibitory effects of cadmium chloride (3. 8-fold) and a range in protection with platinum drugs (from 7-fold with cisplatin, but only 1.3-fold with ZD0473). Overall, the results show that some mechanisms 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 lines, differing mechanisms were apparent. Moreover, ZD0473 possesses distinct cellular pharmacological properties in comparison with cisplatin with respect to reduced interactions with MTs, a thiol-containing species associated with tumour resistance to cisplatin.