Interleukin-1 alpha-induced modulation of topoisomerase I activity and DNA damage: implications in the mechanisms of synergy with camptothecins in vitro and in vivo.

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.