We have reported that ONO-4007, a novel synthetic lipid A derivative with low toxic activities, produced large amount of tumor necrosis factor (TNF)-α selectively in the tumor tissues and brought about complete cures in about 60% of rats bearing TNF-α sensitive KDH-8 cells, which also secreted a large amount of transforming growth factor (TGF)-β. In our present study, to explore ONO-4007 induced Th1-type immune response, we investigated the mRNA expression of interferon (IFN)-γ, Interleukin (IL)-1β, IL-6, IL-10, IL-12 in KDH-8 bearing rats. We next examined the nitric oxide (NO) production. We found that IFN-γ, IL-1β, IL-6 and IL-12 mRNA expression of the tumor tissue were higher in the ONO-4007 treated rats than in phosphate buffer saline (PBS) treated rats. Western blotting also revealed that IL-12 protein production was increased. NO production from peritoneal macrophages were suppressed in tumor-bearing rats, but ONO-4007 restored it up to the normal level. These results suggest that ONO-4007 induces and restores Th1-type immune response through cytokine production cascade, followed by initial TNF-α production, eventually leading to tumor eradication.

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