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.
Morita
S
S
Department of Surgery, Kobe University School of Medicine.
Yamamoto
M
M
Kamigaki
T
T
Saitoh
Y
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D007274:Injections, Intraperitoneal; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D008647:Mesocricetus; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects
D000970:Antineoplastic Agents; D008050:Lipid A; C086889:ONO 4007; D014409:Tumor Necrosis Factor-alpha