ACQUISITION OF CHEMORESISTANCE IN A HUMAN OVARIAN-CARCINOMA CELL-LINEIS LINKED TO A DEFECT IN CELL-CYCLE CONTROL

Chemoresistance is a major concern in cancer erradication; it involves various mechanisms, including defects in the apoptosis program induce d by anticancer drugs. In order to further explore the mechanisms unde rlying the development of chemoresistance in ovarian carcinoma after c isplatin treatment, we established an in vitro model, mimicking a clin ical protocol of administration of cisplatin, Therefore, IGROVI ovaria n carcinoma cells were exposed for 2 hr to the drug and allowed to rec over for several weeks; this way of exposure was reiterated with escal ating doses. We followed changes in cytotoxicity of the drug, cell cyc le kinetics and long-term survival of cells after cisplatin treatment, and found that resistance to cisplatin was not associated with altere d apoptosis pathway, since both cisplatin sensitive and resistant cell s underwent apoptosis in a similar way. Acquisition of resistance to c isplatin was associated with the ability of the treated cells to progr ess through the cell cycle beyond the G(1)/S checkpoint; although most cells died by apoptosis, a few surviving cells proliferated and recol onized the cultures. Compared to sensitive cells, the chemoresistant v ariants were able to override the G(1)/S checkpoint whatever the dose, and the recurrent cells recolonized the cultures much faster. Analysi s of alterations in gene expression suggests that the defect in cell c ycle regulation could take place at the level of the cdk inhibitor p21 (CIP1/WAF1). (C) 1998 Wiley-Liss, Inc.