ONO-4007, an Antitumor Lipid A Analog, Induces Tumor Necrosis Factor-α Production by Human Monocytes Only under Primed State: Different Effects of ONO-4007 and Lipopolysaccharide on Cytokine Production

• Published in: The Journal of pharmacology and experimental therapeutics 1998-01, Vol.284 (1), p.189-195
• Main Authors: Matsumoto, Norihito, Aze, Yoshiya, Akimoto, Akira, Fujita, Tsuneo
• Format: Article
• Language: English
• Subjects: Adult; Antineoplastic Agents - pharmacology; Dose-Response Relationship, Drug; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Humans; Interleukin-1 - biosynthesis; Interleukin-12 - biosynthesis; Interleukin-6 - biosynthesis; Lipid A - analogs & derivatives; Lipid A - pharmacology; Lipopolysaccharides - pharmacology; Monocytes - drug effects; Monocytes - metabolism; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-3565
• DOI: 10.1016/S0022-3565(24)37219-2

ONO-4007 is a synthetic lipid A analog that exhibits strong antitumor activity in several animal models via intratumoral production of tumor necrosis factor (TNF). In the present study, the cytokine-inducing effect of ONO-4007 was investigated in human monocytes that were freshly isolated or had been incubated for 3 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor. ONO-4007 induced slight production of TNF-α, Interleukin (IL)-1β, IL-6 and IL-12 in fresh monocytes but strongly induced TNF-α production in GM-CSF-treated monocytes. Monocytes treated with macrophage colony-stimulating factor were also primed to produce TNF-α in response to ONO-4007. In the production of IL-1β, IL-6 and IL-12, GM-CSF did not show a priming effect. In contrast to ONO-4007, lipopolysaccharide (LPS) induced significant amounts of all these cytokines in fresh monocytes. In whole blood, ONO-4007 failed to induce TNF-α, whereas LPS and LA-15-PP (Escherichia coli-type lipid A) strongly induced TNF-α production. In the GM-CSF-treated monocytes, both elimination of serum from the culture medium and anti-CD14 antibody treatment attenuated LPS-induced TNF-α production but not ONO-4007-induced TNF-α production. This study shows that ONO-4007 activates human monocytes/macrophages to release TNF-α only in a primed state and suggests that ONO-4007 would activate these cells via different pathways from LPS. These differences could mean that ONO-4007 has potent antitumor activity with lower toxicity than LPS.