LEUKEMIC CELL INHIBITION AND MATURATION BY ETHER LIPIDS

人类白血病细胞的一个常见异常是它们不能 分化为功能成熟。取而代之的是，细胞在 功能不成熟的发展状态，并继续扩散。 诱导这些细胞分化并因此移除的能力 从增殖池中提取它们具有深远的治疗意义。 已确定了许多白血病细胞分化的诱导剂 包括二甲基亚砜、佛波酯、杀菌素、丁酸酯、 6-硫代嘌呤、胞嘧啶阿拉伯糖苷和烷基脂质。在所有这些中 烷基类化合物具有最好的临床应用潜力 因为它们对正常细胞相对无毒，而且不会被检测到 致突变特性。我们使用了人类早幼粒细胞白血病细胞 研究脂类介质对HL-60细胞生长和生长的影响 差异化。与结构相关的烷基类脂类已被鉴定 诱导HL-60细胞分化为巨噬细胞样细胞或 粒细胞样细胞。二酰基甘油的烷基连接类似物， 1-0-十六烷基-2-乙酰甘油，刺激分化为 巨噬细胞样细胞和血小板激活因子的类似物， 1-0-hexadecyl-2-0-methyl-sn-glycero-3-phosphocholine，诱导 分化为粒细胞样细胞。我们建议对……进行系统研究 决定细胞生长途径的最低分子要求 差异化。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OKM1单抗的反应将用于确定 分化途径和功能成熟状态。自.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，我们会比较每个人的新陈代谢 HL-60细胞和K562细胞(白血病耐药细胞系)对烷基脂质的作用 以及二倍体人类成纤维细胞。最近的研究表明，蛋白质 蛋白激酶C可能是控制细胞增殖的中心因素 以确定白血病细胞分化的途径。因此， 所有类似物都将被测试对蛋白激酶C的影响。 生长因子、癌基因产物和肿瘤促进剂的作用研究进展 似乎与蛋白激酶C有关。因此，细胞的脂质介质 刺激或抑制蛋白激酶C的分化将是 对确定细胞增殖机制以及 具有潜在重要治疗作用的化合物。

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.