CELL-CYCLE CHANGES ASSOCIATED WITH FORMATION OF PT-DNA ADDUCTS IN HUMAN OVARIAN-CARCINOMA CELLS WITH DIFFERENT CISPLATIN SENSITIVITY

The possible correlation between alterations in cytokinetic response t o cisplatin (CP) treatment and drug resistance in human ovarian carcin oma cell lines was examined. Using dual parameter flow cytometry, we p erformed detailed time-course and dose-response analysis of cell cycle modifications in the parental A2780 and resistant A2780/CP cells expo sed to CP. The data suggested that drug treatment resulted in similar types of cell cycle alterations in cells with different CP sensitivity . Rapid normalization of the cytokinetic pattern in both cell lines at low doses of CP was observed. At higher drug concentrations reversibl e S phase delay predominated, accompanied by blocks in both G1/S and G 2/M and followed by complete normalization of cytokinetic patterns in the surviving cells. CP treatment by lethal doses resulted in almost c omplete S phase block The surviving sells at 72 h accumulated in G2 ph ase. CP-induced cell cycle perturbations, among which the most pronoun ced were alterations in the S phase populations, correlated with the l evel of DNA damage, but not with cell survival in these cell lines, Ho wever, at identical levels of DNA damage, the resistant A2780/CP cell line demonstrated decreased p53 induction and decreased apoptosis comp ared to the parental cell line. Thus, at equivalent levels of DNA dama ge, resistance in this model system correlated with a diminished p53-d ependent apoptotic pathway rather than with differences in cell cycle response. (C) 1997 Wiley-Liss, Inc.