EFFECTS OF INTERLEUKIN-1-ALPHA ON DNA-REPAIR IN HUMAN OVARIAN-CARCINOMA (NIH-OVCAR-3) CELLS - IMPLICATIONS IN THE MECHANISM OF SENSITIZATION OF CIS-DIAMMINEDICHLOROPLATINUM(II)

The cytokine interleukin-1 alpha (IL-1 alpha) showed a cytostatic effect on human ovarian carcinoma cells and significantly enhanced the antiproliferative activity of cis-diamminedichloroplatinum(II) (cisplatin) toward the NIH:OVCAR-3 tumor cell line in culture. The factor of sensitization was 15-20-fold. The maximum levels of sensitization were observed both with simultaneous exposure to cisplatin and IL-1 alpha and with 24-hr pretreatment with IL-1 alpha. Synergy between these agents was diminished when cells were pretreated with an IL-1 alpha-specific receptor antagonist, indicating that synergistic interaction was receptor mediated. Using atomic absorption spectroscopy, we evaluated the cellular accumulation of cisplatin and the DNA platination; the results showed that IL-1 alpha increased cellular accumulation of cisplatin and DNA platination. Cisplatin did not affect IL-1 alpha accumulation in NIH:OVCAR-3 cells. Further studies showed that IL-1 alpha reduced the removal of platinum from DNA. These results strongly suggest that IL-1 alpha inhibits DNA repair, and this decrease in DNA repair may explain, in part, the strong synergistic interaction between IL-1 alpha and cisplatin in NIH:OVCAR-3 cells.