lipid-a and Cell-Transformation--Neoplastic

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.

Topics: Alkaloids; Animals; Base Sequence; Benzoquinones; Calmodulin; Cell Division; Cell Transformation, Neoplastic; In Vitro Techniques; Interleukin-1; Interleukin-6; Lactams, Macrocyclic; Leukemia, Myeloid; Lipid A; Molecular Sequence Data; Protein Kinase C; Protein-Tyrosine Kinases; Quinones; Rats; Rifabutin; RNA, Messenger; Staurosporine; Sulfonamides; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

X-ray induced neoplastic transformation of C3H/10T1/2 cells was suppressed equally by Lipid A and LPS. We examined the effects of several modifiers of arachidonic acid (AA) metabolism in our investigation on the suppression mechanism of LPS. Dexamethasone (DM), an inhibitor of phospholipase A2 (PLA2), abolished the effect of LPS, whereas bromophenacyl bromide (BPB), another inhibitor of PLA2 did not. AA and aspirin neither changed the transformation frequency nor blocked the effect of LPS. TPA, 12-O-tetradecanoyl-phorbol-13-acetate, slightly enhanced radiation transformation, which was diminished by LPS. We also examined the effects of these modifiers on the release of radioactivity from 3H-AA-labeled 10T1/2 cells. No definite correlation was found between the change of AA metabolism and suppression of the transformation frequency by LPS. LPS, however, enhanced dose-dependent myristoylation of the 22 and 67 kDa proteins of 10T1/2 cells.

Topics: Animals; Arachidonic Acid; Cell Transformation, Neoplastic; Depression, Chemical; Lipid A; Lipopolysaccharides; Mice; Mice, Inbred C3H; X-Rays

Expression of the c-fos, c-myc, and c-fms proto-oncogenes has been studied in thioglycollate-elicited murine peritoneal macrophages after exposure to lipopolysaccharide (LPS). After incubation with LPS (20 ng/ml), a transient and rapid induction of the expression of c-fos and c-myc oncogenes could be observed, whereas the RNA levels for c-fms were not affected. Treatment with lipid A, the active moiety of the LPS molecule, increased the c-fos and c-myc expression to a comparable degree. Similar induction of c-fos and c-myc was observed after treatment with phorbol myristate acetate, suggesting that this effect of LPS on murine macrophages might be mediated through stimulation of protein kinase C. Under similar experimental conditions, LPS treatment of macrophages did not trigger DNA synthesis. Treatment with LPS blocked DNA synthesis in macrophages treated with L cell-conditioned medium containing colony-stimulating factor. Thus changes in c-fos and c-myc expression may be elements in the complex series of biochemical events that contribute to macrophage activation and are not necessarily related to induction or priming for cellular proliferation.

Topics: Animals; Cell Transformation, Neoplastic; Cells, Cultured; DNA Replication; Lipid A; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Oncogenes; RNA, Neoplasm

Topics: Animals; Cell Transformation, Neoplastic; Chemical Phenomena; Chemistry; Cytotoxicity, Immunologic; Endotoxins; Escherichia coli; Lipid A; Lipopolysaccharides; Lymphokines; Macrophage-Activating Factors; Macrophages; Mice; Mice, Inbred C3H; Mycobacterium bovis; Neoplasms, Experimental; Periodic Acid