A. Vaisman et al., CELL-CYCLE CHANGES ASSOCIATED WITH FORMATION OF PT-DNA ADDUCTS IN HUMAN OVARIAN-CARCINOMA CELLS WITH DIFFERENT CISPLATIN SENSITIVITY, Cytometry, 27(1), 1997, pp. 54-64
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.