Cell cycle changes associated with formation of Pt-DNA adducts in human ovarian carcinoma cells with different...

The possible correlation between alterations in cytokinetic response to cisplatin (CP) treatment and drug resistance in human ovarian carcinoma cell lines was examined. Using dual parameter flow cytometry, we performed detailed time-course and dose-response analysis of cell cycle modifications in the parental A2780 and resistant A2780/CP cells exposed 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 reversible S phase delay predominated, accompanied by blocks in both G1/S and G2/M and followed by complete normalization of cytokinetic patterns in the surviving cells. CP treatment by lethal doses resulted in almost complete S phase block. The surviving cells at 72 h accumulated in G2 phase. CP-induced cell cycle perturbations, among which the most pronounced were alterations in the S phase populations, correlated with the level of DNA damage, but not with cell survival in these cell lines. However, at identical levels of DNA damage, the resistant A2780/CP cell line demonstrated decreased p53 induction and decreased apoptosis compared to the parental cell line. Thus, at equivalent levels of DNA damage, resistance in this model system correlated with a diminished p53-dependent apoptotic pathway rather than with differences in cell cycle response.