A new synthetic lipid A analog, ONO-4007, stimulates the production of tumor necrosis factor-alpha in tumor tissues, resulting in the rejection of transplanted rat hepatoma cells.
ONO-4007 is a new synthetic lipid A derivative with low endotoxic activities. We have examined the therapeutic effects of ONO-4007 on rat hepatocellular carcinoma KDH-8 cells, rat fibrosarcoma KMT-17 cells and rat mammary adenocarcinoma SST-2 cells in vivo. Multiple systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after tumor implantation of KDH-8 and SST-2 cells, and on days 5, 10 and 15 after tumor implantation of KMT-17 cells. ONO-4007 showed significant therapeutic effects on KDH-8 cells; by the administration of ONO-4007 (2.5 mg/kg) 70% of rats were cured and by the administration of ONO-4007 (5 mg/kg) 50% of rats were cured. Furthermore, the ONO-4007 treatment prolonged the mean survival time of KDH-8-bearing rats. However, ONO-4007 had no effect on KMT-17 and SST-2 cells, and it had no direct effect on the growth of KDH-8 cells in vivo. Albeit the stimulation with ONO-4007 induced mRNA expressions of interleukin (IL)-1alpha, IL-6 and tumor necrosis factor (TNF)-a, those of IL-2, IL-4, IL-10 and interferon (IFN)-gamma were not induced. Using a bioassay, we found that the production of TNF-alpha in the tumor tissues was induced by ONO-4007 in a dose-dependent manner. KDH-8 cells were sensitive to human natural TNF-alpha in vitro. However, KMT-17 and SST-2 cells were resistant against TNF-alpha in vitro. These results suggest that ONO-4007 is therapeutically useful for the treatment of TNF-alpha-sensitive tumors.
Kuramitsu
Y
Y
Laboratory of Pathology, Cancer Institute, Hokkaido University School of Medicine, Kita-ku, Sapporo, Japan.
Nishibe
M
M
Ohiro
Y
Y
Matsushita
K
K
Yuan
L
L
Obara
M
M
Kobayashi
M
M
Hosokawa
M
M
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy; D007202:Indicators and Reagents; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008113:Liver Neoplasms / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D016207:Cytokines; D007202:Indicators and Reagents; D008050:Lipid A; C086889:ONO 4007; D012334:RNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha