CELL-CYCLE PERTURBATIONS IN CISPLATIN-SENSITIVE AND RESISTANT HUMAN OVARIAN-CARCINOMA CELLS FOLLOWING TREATMENT WITH CISPLATIN AND LOW-DOSERATE IRRADIATION

Purpose: To investigate cell cycle pertubations in plateau-phase human ovarian carcinoma cells following treatment with cisplatin, low dose- rate irradiation (LDRI), or combined cisplatin and LDRI, in order to u nderstand cell cycle mechanisms by which these two treatment modalitie s interact. Methods: Human ovarian carcinoma cells sensitive (A2780) a nd resistant (2780(CP)) to cisplatin were grown to plateau phase and g iven protracted cisplatin treatments (A2780 0.7 and 2 mu g/ml; 2780(CP ) 5 and 15 mu g/ml) and/or LDRI (0.41 cGy/min). Cell cycle distributio n following treatment was determined by two-parameter flow cytometry, based on bromodeoxyuridine (BrdU) uptake and DNA content using propidi um iodide staining. Results: The cisplatin-sensitive A2780 cells expos ed to cisplatin alone for up to 28 h showed depletion of the G1 fracti on and accumulation in S-phase, although the percentage of S-phase cel ls actively incorporating BrdU dropped to almost zero. The cisplatin-r esistant 2780(CP) cells exposed to cisplatin alone showed a G1 arrest when exposed to 15 mu g/ml, but not when exposed to 5 mu g/ml. LDRI al one caused little cell cycle redistribution different from controls in either cell line. When LDRI was combined with cisplatin, no significa nt cell cycle redistribution was observed, apart from a decline in the actively incorporating S-phase fraction. Conclusions: Cisplatin cause d A2780 cells to accumulate in nonincorporating S-phase, with no evide nce of G1 arrest. Cisplatin-resistant 2780(CP) cells showed a G1 block when exposed to a high enough cisplatin concentration. This could ind icate a mechanism of cisplatin resistance in these cells. LDRI alone o r in combination with cisplatin did not result in significant cell cyc le redistribution.