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.

Abstract

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.

• Authors: Y Kuramitsu, M Nishibe, Y Ohiro, K Matsushita, L Yuan, M Obara, M Kobayashi, M Hosokawa
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 8 Issue 5 Pg. 500-8 (Jun 1997) ISSN: 0959-4973 [Print] England
• PMID: 9215614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytokines
• Indicators and Reagents
• Lipid A
• ONO 4007
• RNA, Neoplasm
• Tumor Necrosis Factor-alpha

Topics

• Adenocarcinoma (drug therapy)
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Hepatocellular (pathology)
• Cell Survival (drug effects)
• Cytokines (biosynthesis)
• Female
• Fibrosarcoma (drug therapy)
• Indicators and Reagents
• Lipid A (analogs & derivatives, pharmacology)
• Liver Neoplasms (pathology)
• Mammary Neoplasms, Experimental (drug therapy)
• Neoplasm Transplantation
• Polymerase Chain Reaction
• RNA, Neoplasm (biosynthesis)
• Rats
• Rats, Wistar
• Spleen (drug effects, metabolism)
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (biosynthesis)