EFFECT OF INTERLEUKIN-1-ALPHA AND TUMOR-NECROSIS-FACTOR-ALPHA ON CISPLATIN-INDUCED ERCC-1 MESSENGER-RNA EXPRESSION IN A HUMAN OVARIAN-CARCINOMA CELL-LINE

Enhanced expression of the human excision repair enzyme ERCC-1 is asso ciated with cellular and clinical resistance to cisplatin in human ova rian cancer. High levels of expression of ERCC-1 appear to be associat ed with increased activity of the nucleotide excision repair pathway. We therefore began to examine the effect of some cisplatin resistance modulators on cisplatin-induced ERCC-1 mRNA expression in the human ov arian carcinoma cell line, A2780/CP70. Cisplatin exposure to A2780/CP7 0 cells in culture resulted in a four-to five-fold induction for stead y-state ERCC-1 mRNA, that was dose-and time-dependent. The biological agents interleukin (IL)-1a and tumour necrosis factor (TNF)-a have bee n shown to enhance cisplatin cytotoxicity in vitro. IL-la inhibited ci splatin induction of ERCC-1 mRNA levels in our system. The effect of I L-1a was sequence dependent in that the maximum inhibitory effect was observed with 24-hour pretreatment with IL-1a. By contrast, TNF-a had little effect on ERCC-1 mRNA induction by cisplatin. Low-temperature h yperthermia (42 degrees C) almost completely suppressed ERCC-1 mRNA in duction in these cells. These findings suggest that the enhancement ef fect of some agents on cisplatin sensitivity in ovarian tumour Cells m ay be through downregulating ERCC-1 expression.