CHARACTERIZATION OF THE P53 STATUS, BCL-2 EXPRESSION AND RADIATION AND PLATINUM DRUG-SENSITIVITY OF A PANEL OF HUMAN OVARIAN-CANCER CELL-LINES

The P53 gene is frequently mutated in late stage ovarian cancer and ha s been proposed as a determinant of radiation and chemosensitivity. We have therefore determined the p53 functional status, P53 sequence, ra diation sensitivity and cytotoxicity of cisplatin and the novel platin um analogue, AMD473, in a panel of 6 human ovarian cancer cell lines. Constitutive p53 protein levels were low in A2780, CH1, LK1, LK2 and P A1 but were markedly induced following irradiation. In OVIP, constitut ive p53 protein was readily detectable and levels were induced slightl y following irradiation. P21(WAFI/CIPI) and MDM-2 mRNA were constituti vely expressed in all the cell lines and expression was induced marked ly following irradiation. There was marked radiation induced G(I)/S ar rest in A2780 but only partial arrests in CH1, LK1, LK2, PA1 and OVIP lines. No mutations were found in A2780, CH1, LK1, LK2 and PA1 cells b y single-strand conformational polymorphism (SSCP) analysis but a hete rozygous point mutation was found in exon 5 of OVIP. All the cell line s were radiation sensitive and also relatively sensitive to cisplatin; however, OVIP was the most resistant being consistent with its hetero zygous P53 status. AMD473 was less potent than cisplatin but a similar pattern of drug sensitivity was observed with the exception of LK2, w hich was resistant. CH1, LK1, LK2 and PA1 all expressed BCL-2 protein but there was no expression in A2780 and OVIP, Our results suggest an overall association between wild type P53 and radiation and platinum d rug sensitivity in these ovarian cancer cell lines. (C) 1998 Wiley-Lis s, Inc.