Synthetic lipid A produces antitumor effect in a hamster pancreatic carcinoma model through production of tumor necrosis factor from activated macrophages

The antitumor effect and biological activities of a newly synthesized lipid A analogue (ONO-4007) were investigated in a hamster pancreatic carcinoma model. Marked and dose-dependent inhibition of tumor growth was achieved by i.p. injection twice a week for 3 weeks of 10, 30 or 50 mg/kg of ONO-4007. Endogenous tumor necrosis factor (TNF) activities induced by ONO-4007 were significantly greater in tumor than in serum, spleen and liver. TNF production by macrophages stimulated with ONO-4007 after culture was much greater when culture was performed in the presence of hamster pancreatic carcinoma cells (no cell-to-cell contact). It was further found that the cytotoxic activity of TNF secreted by macrophages cultured with cancer cells was inhibited in the presence of anti-TNF neutralizing antibodies. These findings suggest that ONO-4007 displays antitumor effects by stimulating production of endogenous TNF in tumor macrophages, possibly through activation by soluble macrophage-stimulating factors in cancer cells.