Interleukin-1a showed a cytostatic effect on human ovarian carcinoma cells, and significantly enhanced the antiproliferative activity of cis- diamminedichloro-platinum (II) (cisplatin) towards the NIH: OVCAR-3 tumor cell line in culture. The factor of sensitization was 15 to 20-fold. The maximum levels of sensitization were observed during both simultaneous exposure of cisplatin and IL-1a, with 24 hrs pretreatment with IL-1a. Synergy between these agents was diminished when cells were pretreated with an IL-1a specific receptor antagonist, indicating that synergistic interaction was receptor mediated. Cellular accumulation of cisplatin and the DNA platination was evaluated and results showed that IL-1a induced an increase in cellular accumulation of cisplatin and DNA platination. In addition, we found that IL-1a treatment inhibited the removal of platinum from the cellular DNA. Interleukin-1a significantly potentiated cytotoxicity of carboplatin (8-fold) during simultaneous drug exposure in human ovarian NIH:OVCAR-3 cancer cell lines in vitro. Treatment of human ovarian tumor cells grown as xenografts in nude mice with IL-1a followed by carboplatin at minimally toxic doses significantly (2-3-fold) enhanced antitumor activity of either agent alone, indicating that IL-1a-drug combinations may be potentially more effective for the treatment of ovarian tumors, including those difficult to cure in the clinic.
