""""""""DISCONTINUED Interleukin-1a showed a cytostatic effect on human ovarian carcinoma cells, and significantly enhanced the antiproliferative activity of 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. IL-1a significantly potentiated cytotoxicity of carboplatin (8-fold) during simultaneous drug exposure in human ovarian NIH:OVCAR-3 cancer cell lines in vitro. Cell cycle analysis of NIH:OVCAR-3 cells treated with either IL-1a or CDDP and combinations indicated significant accumulation of cells in G1 phase of the cell cycle and a decrease in S phase of the cell cycle. Treatment of ovarian cells with CDDP or IL-1a alone decreased the steady-state expression of both c-myc RNA and c- myc protein and caused significant degradation of the genomic DNA into internucleosomal sized DNA fragments, indicating apoptosis. Significantly, more DNA fragmentation was observed in the presence of CDDP and IL-1a. IL-1a and CDDP treatment resulted in a significant induction of p53 protein in OVCAR-3 cells in a time- and dose-dependent manner. However, p21 was not induced under these conditions. These studies suggest that IL-1a may kill ovarian OVCAR-3 tumor cells by inducing a blockade at G1/S of the cell cycle, inducing p53-dependent apoptosis and damaging c-myc gene. The synergistic interactions of IL-1a with CDDP may involve the enhancement of this apoptosis of tumor cells in G1 phase of the cell cycle in p53-dependent pathways.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 single agents alone. These studies indicate that IL-1a-drug combinations may be potentially more effective for the treatment of ovarian tumors, including those difficult to cure in the clinic.""""""""
