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.