LEUKEMIC CELL INHIBITION AND MATURATION BY ETHER LIPIDS

人类白血病细胞的一种常见异常是它们不能 分化至功能成熟。 相反，细胞被阻止在一个 功能不成熟的发展状态，并继续增殖。 诱导这些细胞分化的能力， 将它们从增殖池中分离出来具有深远的治疗意义。 许多诱导白血病细胞分化已被确定 包括二甲亚砜、佛波醇二酯、杀鱼素、丁酸盐 6-巯基嘌呤、阿糖胞苷和烷基脂质。 所有这些 化合物的烷基脂质具有最好的临床应用潜力 因为它们对正常细胞相对无毒， 诱变特性 我们用人类早幼粒细胞白血病细胞 HL-60细胞系，研究脂质介质对细胞生长和增殖的影响。 分化 结构相关的烷基脂质已被确定 其诱导HL-60细胞分化为巨噬细胞样或 粒细胞样细胞 一种烷基连接的甘油二酯类似物， 1-O-十六烷基-2-乙酰基-甘油，刺激分化为 巨噬细胞样细胞和血小板活化因子的类似物， 1-O-十六烷基-2-O-甲基-sn-甘油-3-磷酸胆碱，诱导 向粒细胞样细胞分化。 我们建议系统地研究 决定蛋白质合成途径的最低分子量要求 分化 几项生化试验，包括吞噬作用、H202 生产，花生四烯酸代谢，磷蛋白谱和 与OKM 1单克隆抗体的反应将用于确定 分化途径和功能成熟状态。 以来 新化合物的有效性和选择性可能取决于它们的 抵抗细胞降解，我们将比较每种代谢 HL-60细胞、K562细胞（耐药白血病细胞系） 和二倍体人成纤维细胞。 研究表明，蛋白质 激酶C可能是控制细胞增殖的中心因子， 决定白血病细胞分化的途径。 因此，我们认为， 测试所有类似物对蛋白激酶C的作用。 的机制 生长因子、肿瘤产品和肿瘤促进剂的作用， 似乎与蛋白激酶C有关 因此，细胞脂质介质 刺激或抑制蛋白激酶C的分化将是 在确定细胞增殖机制以及 潜在的重要治疗化合物。

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.