Lipid A and the lipid A analogue anti-tumour compound ONO-4007 induce nitric oxide synthase in vitro and in vivo.
The ability of lipid A and the antitumour compound, ONO-4007 (sodium2-deoxy-2-[3S-(9-phenylnonanoyloxy)tetradecanoyl] amino-3-O-(9phenylnonanoyl)-D-glucopyranose 4-sulphate) to induce nitric oxide (NO) synthase was investigated in vitro and in vivo, in comparison to the effects of lipopolysaccharide and di- and monophosphoryl lipid A. In J744.2 macrophages, lipopolysaccharide, di-and monophosphoryl lipid A and ONO-4007 (10(-9) - 10(-5) g/ml) alone, or in combination with interferon-gamma, induced NO synthase (order of potency: lipopolysaccharide > diphosphoryl lipid A > monophosphoryl lipid A > ONO-4007). ONO-4007 increased the activity of the inducible NO synthase in the lung of anesthetised rats (20% of the increased caused by bacterial lipopolysaccharide). Thus, ONO-4007 is a weak inducer of the inducible isoform of NO synthase in vitro and in vivo. The finding that di- and monophosphoryl lipid A also induce NO synthase indicates that the lipid A moiety of lipopolysaccharide contributes to the induction of NO synthase by lipopolysaccharide. The induction of NO synthase by ONO-4007, resulting in the formation of cytotoxic NO may contribute to the antitumour activity of the compound.
Hattori
Y
Y
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, UK.
Szabó
C
C
Gross
S
S
Thiemermann
C
C
Vane
J R
JR
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D008050:Lipid A; D008070:Lipopolysaccharides; C086889:ONO 4007; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase