Intratumoral tumor necrosis factor induction and tumor growth suppression by ONO-4007, a low-toxicity lipid A analog.
BACKGROUND
ONO-4007 is a lipid A analog with low toxicity.


METHODS
The antitumor activity and tumor necrosis factor (TNF)-inducing activity of ONO-4007 were compared with those of lipopolysaccharide (LPS) in WKAH rats bearing KDH-8 hepatoma cells.


RESULTS
Weekly injections of ONO-4007 (3 and 10 mg/kg i.v.) suppressed tumor growth, but LPS (0.01 and 0.1 mg/kg i.v.) did not. A single injection of ONO-4007 (3 and 10 mg/kg i.v.) into tumor-bearing rats induced higher levels of endogenous TNF production in tumor tissues than LPS (0.001, 0.01 and 0.1 mg/kg i.v.). Repeated injections of LPS caused a reduction of TNF production in tumor tissues, whereas the reduction by ONO-4007 was less remarkable than that by LPS. Intratumoral injections of anti-rat TNF-alpha antibody attenuated the antitumor effect of ONO-4007.


CONCLUSIONS
The antitumor effect of ONO-4007 is more pronounced than that of LPS and the effect is mediated by TNF produced in tumor tissues.
Matsumoto
N
N
Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Japan.
Oida
H
H
Aze
Y
Y
Akimoto
A
A
Fujita
T
T
D000818:Animals; D000906:Antibodies; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004008:Diclofenac / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D007275:Injections, Intravenous; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D000906:Antibodies; D000970:Antineoplastic Agents; D008050:Lipid A; D008070:Lipopolysaccharides; C086889:ONO 4007; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D007213:Indomethacin