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-1 is associated with cellular and clinical resistance to cisplatin in human ovarian cancer. High levels of expression of ERCC-1 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-1 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-1 mRNA, that was dose- and time-dependent. The biological agents interleukin (IL)-1 alpha and tumour necrosis factor (TNF)-alpha have been shown to enhance cisplatin cytotoxicity in vitro. IL-1 alpha inhibited cisplatin induction of ERCC-1 mRNA levels in our system. The effect of IL-1 alpha was sequence dependent, in that the maximum inhibitory effect was observed with 24-hour pretreatment with IL-1 alpha. By contrast, TNF-alpha had little effect on ERCC-1 mRNA induction by cisplatin. Low-temperature hyperthermia (42 degrees C) almost completely suppressed ERCC-1 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-1 expression.