Sensitization by interleukin-1alpha of carboplatinum anti-tumor activity against human ovarian (NIH:OVCAR-3) carcinoma cells in vitro and in vivo.

Cytokines are directly cytotoxic to tumor cells in vitro and in vivo, and interleukin-1alpha (IL-1alpha) potentiates the cytotoxicity of a number of clinically active drugs in several human tumor cells, including carcinomas of the breast and ovary. In this study, we found that IL-1alpha potentiated the cytotoxicity of carboplatin in human ovarian NIH:OVCAR-3 cancer cells during simultaneous drug exposure in vitro. Human ovarian carcinoma NIH:OVCAR-3 cells are resistant to clinically relevant concentrations of chemotherapeutic agents, including cisplatin. Both carboplatin and IL-1alpha as single agents inhibited the growth of NIH:OVCAR-3 cells grown as xenograft in nude mice; however, carboplatin was more effective in delaying tumor growth, and this inhibition was dose-dependent. Treatment with IL-1alpha followed by carboplatin caused a significant delay in tumor growth, resulting in a significant enhancement (4-fold) of the anti-tumor effect of carboplatin. In vitro potentiation of carboplatin cytotoxicity by IL-1alpha did not involve formation of nitric oxide as IL-1 or combinations of IL-1 with carboplatin failed to modulate basal nitric oxide production in OVCAR-3 cells. Potentiation of the anti-tumor activity of carboplatin by IL-1alpha was due to a significant (3- to 4-fold) increase in the accumulation of total Pt in IL-1-treated tumor xenograft, resulting in a 2-fold increase in DNA-Pt adduct formation in these tumors. In contrast, IL-1alpha had no significant effect on DNA-Pt adduct formation in the kidney. The potent synergy of IL-1alpha and carboplatin in vitro and in vivo against ovarian carcinoma cells suggests that combinations of carboplatinum and interleukin-1alpha may be effective against this disease in the clinic.