ONO-4007, a synthetic lipid A analog, induces Th1-type immune response in tumor eradication and restores nitric oxide production by peritoneal macrophages.
We have reported that ONO-4007, a novel synthetic lipid A derivative with low toxic activities, produced large amount of tumor necrosis factor (TNF)-alpha selectively in the tumor tissues and brought about complete cures in about 60% of rats bearing TNF-alpha sensitive KDH-8 cells, which also secreted a large amount of transforming growth factor (TGF)-beta. In our present study, to explore ONO-4007 induced Th1-type immune response, we investigated the mRNA expression of interferon (IFN)-gamma, Interleukin (IL)-1beta, IL-6, IL-10, IL-12 in KDH-8 bearing rats. We next examined the nitric oxide (NO) production. We found that IFN-gamma, IL-1beta, 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-alpha production, eventually leading to tumor eradication.
Matsushita
Kazuhiro
K
Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan. kmatsushita@nyc.odn.ne.jp
Kuramitsu
Yasuhiro
Y
Ohiro
Yoichi
Y
Kobayashi
Ichizo
I
Watanabe
Tae
T
Kobayashi
Masanobu
M
Hosokawa
Masuo
M
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018417:Th1 Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007375:Interleukin-1; D015850:Interleukin-6; D008050:Lipid A; C086889:ONO 4007; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma