lipid-a and Leukemia--Myeloid

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

A clone of mouse leukemia M1 cells was induced to differentiate by lipopolysaccharide (LPS) (LPS-sensitive clone) while another clone of the same cells was resistant (LPS-resistant clone). LPS and lipid A preparations from Pseudomonas diminuta and Pseudomonas vesicularis were as active as Escherichia coli LPS in the induction of differentiation of the LPS-sensitive clone. Synthetic lipid A precursor Ia (compound 406), which has no interleukin 1 (IL-1)-inducing activity toward monocytes, had strong differentiation-inducing activity toward the LPS-sensitive clone. The combined treatment of the LPS-sensitive clone with LPS and recombinant tumor necrosis factor (rTNF) did not further increase the degree of differentiation induced by LPS alone. By contrast, the LPS-resistant clone was markedly induced to differentiate by LPS in the presence of rTNF. Combined treatment of the LPS-resistant clone with LPS and other cytokines such as recombinant IL-1 alpha, recombinant granulocyte colony-stimulating factor, and interferon-gamma was not effective in inducing marked synergistic differentiation. These results raise the possibility that rTNF changes the sensitivity of M1 cells to induction of differentiation by LPS.

Topics: Animals; Cell Differentiation; Clone Cells; Drug Resistance; Drug Synergism; Humans; Leukemia, Myeloid; Lipid A; Lipopolysaccharides; Mice; Receptors, Cell Surface; Receptors, Tumor Necrosis Factor; Structure-Activity Relationship; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Topics: Animals; Bone Marrow Cells; Cell Differentiation; Cell Membrane; Cells, Cultured; Chromosome Aberrations; Chromosome Disorders; Colony-Stimulating Factors; Dexamethasone; Glycoproteins; Granulocytes; Hematopoietic Stem Cells; Humans; Leukemia, Experimental; Leukemia, Myeloid; Leukocytes; Lipid A; Macrophages; Mice