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

Yoshiyuki Hattori, Csaba Szabó, Steven S. Gross, Christoph Thiemermann, John R. Vane

    Research output: Contribution to journalArticle

    25 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)83-90
    Number of pages8
    JournalEuropean Journal of Pharmacology: Molecular Pharmacology
    Volume291
    Issue number2
    DOIs
    StatePublished - Oct 15 1995

    Keywords

    • Anti-cancer drug
    • Cancer
    • Chemotherapy
    • Cytotoxicity
    • Endotoxin
    • Nitric oxide (NO) synthase

    ASJC Scopus subject areas

    • Pharmacology

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