Abstract
We have examined the differentiation-inducing effects of ONO-4007, a new synthetic lipid A derivative with low endotoxic activities, on a rat myelomonocytic cell line, c-WRT-7, in vitro and in vivo. ONO-4007 induced the differentiation of c-WRT-7 cells into macrophage-like cells and inhibited the proliferation of c-WRT-7 cells in vitro. Stimulation with ONO-4007 induced messenger RNA expression of interleukin-1 alpha (IL-1 alpha), IL-6, and tumor necrosis factor-alpha (TNF-alpha), which have been reported to induce differentiation of several leukemia cell lines. However, autocrine production of these cytokines may not be involved in the mechanisms of differentiation induced by ONO-4007, because the treatment with IL-1 alpha, IL-6, or TNF-alpha does not induce the differentiation of c-WRT-7 cells. In vivo treatment by intravenous administration of ONO-4007 resulted in a significant prolongation of survival time of the rats inoculated intravenously with c-WRT-7 cells compared with that of untreated rats. These results suggest that ONO-4007 can be therapeutically useful for the treatment of leukemia.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / pharmacology
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Animals
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Base Sequence
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Benzoquinones
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Calmodulin / antagonists & inhibitors
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Cell Division / drug effects
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Cell Division / physiology
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Cell Transformation, Neoplastic / pathology*
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In Vitro Techniques
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Interleukin-1 / genetics
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Interleukin-1 / metabolism
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Interleukin-1 / pharmacology
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Interleukin-6 / pharmacology
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Lactams, Macrocyclic
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Leukemia, Myeloid / metabolism
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Leukemia, Myeloid / pathology*
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Leukemia, Myeloid / physiopathology
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Lipid A / analogs & derivatives*
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Lipid A / metabolism
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Lipid A / pharmacology
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Molecular Sequence Data
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Protein Kinase C / antagonists & inhibitors
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Quinones / pharmacology
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RNA, Messenger / analysis
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RNA, Messenger / genetics
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Rats
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Rifabutin / analogs & derivatives
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Staurosporine
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Sulfonamides / pharmacology
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Alkaloids
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Benzoquinones
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Calmodulin
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Interleukin-1
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Interleukin-6
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Lactams, Macrocyclic
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Lipid A
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ONO 4007
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Quinones
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RNA, Messenger
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Sulfonamides
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Tumor Necrosis Factor-alpha
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Rifabutin
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W 7
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herbimycin
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Protein-Tyrosine Kinases
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Protein Kinase C
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Staurosporine