Effect of interleukin-1 alpha and tumour necrosis factor-alpha on cisplatin-induced ERCC-1 mRNA expression in a human ovarian carcinoma cell line.

Enhanced expression of the human excision repair enzyme ERCC-I is associated with cellular and clinical resistance to cisplatin in human ovarian cancer. High levels of expression of ERCC-I appear to be associated 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-I mRNA expression in the human ovarian carcinoma cell line, A2780/CP70. Cisplatin exposure to A2780/CP70 cells in culture resulted in a four- to five-fold induction for steady-state ERCC-I mRNA, that was dose- and time-dependent. The biological agents interleukin (IL)-1α and tumour necrosis factor (TNF)-α have been shown to enhance cisplatin cytotoxicity in vitro. IL-1α inhibited cisplatin induction of ERCC-1 mRNA levels in our system. The effect of IL-1α was sequence dependent, in that the maximum inhibitory effect was observed with 24-hour pretreatment with IL-la. By contrast, TNF-α had little effect on ERCC-I mRNA induction by cisplatin. Low-temperature hyperthermia (42°C) almost completely suppressed ERCC-I mRNA induction in these cells. These findings suggest that the enhancement effect of some agents on cisplatin sensitivity in ovarian tumour cells may be through downregulating ERCC-I expression.