DECREASED CYTOTOXIC EFFECTS OF DOXORUBICIN IN A HUMAN OVARIAN CANCER-CELL LINE EXPRESSING WILD-TYPE P53 AND WAF1/CIP1 GENES

The cytotoxicity of Doxorubicin and cis-dichloro-diammine-platinum (DDP) was evaluated in clones, obtained from a human ovarian cancer cell line transfected with a temperature-sensitive P53 mutant, which express mutant p53 at 37 degrees C and wild-type-like p53 at 32 degrees C. DDP was equally active in cells not expressing p53 (SKN) or cells expressing a mutated form of p53 (SK23a kept at 37 degrees C) or a wild-type-like form of p53 (SK23a cells kept at 32 degrees C). In contrast, Doxorubicin was less cytotoxic: in cells expressing wild type p53 than in cells expressing no p53 or mutated p53. This reduction was not due to a decreased intracellular accumulation or to a faster efflux of Doxorubicin. Topoisomerase II was found to be present in the same amount in all the systems utilized and to be functionally active, thus not accounting for the observed effect of Doxorubicin. A clear induction of WAF1/CIP1 and GADD45 genes in cells expressing wild-type p53 after Doxorubicin treatment was found. DDP, which was equally active in the cells utilized, caused an increase in the transcription only of GADD45 gene but not of WAF1/CIP1 gene. Doxorubicin was also able to induce the transcription of WAFI/CIP1 gene in SKN cells (not expressing p53) or in SK23a cells at 37 degrees C (expressing mutated p53), indicating that the expression of this gene also, in some tumor-cell lines, is not necessarily or uniquely induced by wild-type p53. (C) 1995 Wiley-Liss, Inc.