ZD0473 is a new generation
platinum agent that, in preclinical studies, shows evidence of an extended spectrum of anti-
tumor activity and overcomes
platinum resistance mechanisms. The
drug contains a bulky methylpyridine
ligand at its
platinum center, which is responsible for its ability to overcome
platinum resistance. We examined the growth inhibitory effects of
ZD0473 in human
lung cancer cell lines resistant to
cisplatin in vitro. Four
cisplatin resistant human
lung cancer cell lines (PC-14/CDDP, SBC-3/CDDP, PC-9/CDDP, H69/CDDP) showed the expected resistance to
cisplatin but were non-cross, or much less, resistant to
ZD0473, as determined by an MTT assay. A reduction in the intracellular accumulation of
cisplatin, but not of
ZD0473, was observed in the PC-14/CDDP cells compared with the levels in PC-14 parental cells. The reduction in
cisplatin accumulation is considered a major mechanism of the acquired
cisplatin resistance in PC-14/CDDP cells. Therefore, the increase in
platinum accumulation is considered a possible mechanism underlying the activity of
ZD0473 in
cisplatin-resistant cells.
Glutathione-mediated resistance to
cisplatin was also overcome by
ZD0473 in PC-14/CDDP cells. In addition, we showed that the intraperitoneal administration of
ZD0473 at its maximum tolerable dose in mice produced a marked in vivo antitumor activity against
cisplatin-resistant PC-14/CDDP
tumors. These results suggest that
ZD0473 may be a potent agent in human
lung cancer cells with multifactorial
cisplatin resistance.