A common abnormality of human leukemic cells is their inability to differentiate to functinal maturity. Instead, the cells are blocked at a functionally immature state of development and continue to proliferate. The ability to induce these cells to differentiate and therefore remove them from the proliferative pool is of profound therapeutic importance. Numerous inducers of leukemic cell differentiation have been identified including dimethyl sulfoxide, phorbol diesters, teleocidin, butyrate, 6-mercaptopurine, cytosine arabinoside and alkyl lipids. Of all these compounds the alkyl lipids have the best potential for clinical application because they are relatively nontoxic to normal cells and have no detectable mutagenic properties. We have used the human promyelocytic leukemia cell line HL-60 to study the effects of lipid mediators on cell growth and differentiation. Structurally-related alkyl lipids have been identified which induce HL-60 cells to differentiate to eiher macrophage-like or granulocyte-like cells. An alkyl-linked analog of diacylglycerol, 1-0-hexadecyl-2-acetyl-glycerol, stimulates differentiation to macrophage-like cells and an analog of platelet activating factor, 1-0-hexadecyl-2-0-methyl-sn-glycero-3-phosphocholine, induces differentiation to granulocyte-like cels. We propose a systematic study of the minimum molecular requirements which determine the pathway of differentiation. Several biochemical tests including phagocytosis, H202 production, arachidonic acid metabolism, phosphoprotein profile and reaction with OKM1 monoclonal antibody will be used to determine the pathway of differentiation and the state of functional maturity. Since the effectiveness and selectivity of new compounds may depend on their resistance to cellular degradation, we will compare the metabolism of each alkyl lipid by HL-60 cells, by K562 cells (a resistant leukemic cell line) and by diploid human fibroblasts. Recent studies indicate that protein kinase C may be a central factor in the control of cell proliferation and in determining the pathway of leukemic cell differentiation. Therefore, all analogs will be tested for effects on protein kinase C. The mechanisms of action of growth factors, oncognee products and tumor promoters now appear to involve protein kinase C. Thus, lipid mediators of cell differentiation which stimulate or inhibit protein kinase C will be of great value in determining the mechanism of cell proliferation as well as potentially important therapeutic compounds.
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