Lipid A and the lipid A analogue anti-tumour compound ONO-4007 induce nitric oxide synthese in vitro and in vivo

Abstract

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 lipopolysacchride and di-and monophosphoryl lipid A. In J774.2 macrophages, lipopolysaccharide, di-and monophosphoryl lipid A and ONO-4007 (10⁻⁹-10⁻⁵ g/ml) alone, or in combination with interferion-γ, induced NO synthese (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 increase 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 contibute to the antitumour activity of the compound.