Abstract
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 viadifferent pathways from LPS. These differences could mean that ONO-4007 has potent antitumor activity with lower toxicity than LPS.
Footnotes
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Send reprint requests to: Norihito Matsumoto, 50-10 Yamagishi, Mikuni-cho, Sakai-gun, Fukui, 913, Japan.
- Abbreviations:
- ELISA
- enzyme-linked immunosorbent assay
- FCS
- fetal calf serum
- GM-CSF
- granulocyte-macrophage colony-stimulating factor
- IL
- interleukin
- LBP
- LPS-binding protein
- LPS
- lipopolysaccharide
- M-CSF
- macrophage colony-stimulating factor
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- TNF
- tumor necrosis factor
- Received July 8, 1997.
- Accepted September 5, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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