Abstract

Studies have shown that cytokines are directly cytotoxic to tumor cells in vitro and in vivo and that interleukin-1 alpha (IL-1 alpha) potentiates the cytotoxicity of certain clinically active drugs in a number of human tumor cells, including carcinomas of breast and ovary. We found that interleukin-1 alpha potentiated cytotoxicity of camptothecin (4-5-fold) during simultaneous drug exposure in human ovarian NIH:OVCAR-3 cancer cells in vitro. Studies indicated that IL-1 alpha significantly increased topoisomerase I-catalyzed camptothecin-induced DNA cleavable complexes in the ovarian cell line, which was not due increased intracellular camptothecin as IL-1 alpha failed to effect cellular uptake of camptothecin. Pretreatment of the ovarian cells with IL-1 alpha did not result in increased expressions of mRNA for the topoisomerase I gene, whereas a small increase (approximately 1.5-fold) in the expression of topoisomerase I protein was observed, suggesting that IL-1 modulated the activity of topoisomerase I for the observed increase in cleavable complex formation. Treatment of human ovarian tumor cells grown as xenografts in nude mice with IL-1 alpha followed by CPT-11 at minimally toxic doses significantly (5-6-fold) enhanced antitumor activity of either agent alone. Because camptothecins are active against solid tumors in vivo, combinations of IL-1 alpha with these active drugs may lead to more effective treatment of ovarian cancers in the clinic.