EFFECTS OF FATTY ACID OXIDATION PRODUCTS ON NEOPLASTIC CELLS

脂肪酸氧化产物对肿瘤细胞的影响

• 批准号: 6203297
• 负责人: ARTHUR A. SPECTOR
• 金额: $ 11.34万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-31 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203297
• 关键词: MCF7 cell; acute monocytic leukemia; adduct; antineoplastics; ascorbate; calcium flux; cyclic nucleoside monophosphate; drug interactions; eicosanoids; electron spin resonance spectroscopy; high performance liquid chromatography; iron; lipid peroxides; micelles; neoplasm /cancer pharmacology; nutrition related tag; oxidative stress; phospholipids; tissue /cell culture; tocopherols; unsaturated fatty acids

This project is based on the hypothesis that the oxidized fatty acid products formed as a result of lipid peroxidation contribute to the overall cytotoxic effect of certain anticancer therapies. The overall objectives are to identify the 'stable' lipid peroxidation products formed in intact neoplastic cells exposed to oxidative stress, investigate how these cells respond to the accumulation of polyunsaturated fatty acid (PUFA) peroxidation products, and determine whether retention of these products contributes to the cytotoxic effects of therapies that induce lipid peroxidation. The primary experimental model will be the U937 human monocytic leukemia cell line. The first aim is to identify the radical adduct formed by U937 cell enriched with PUFA. Next, we will determine whether lipid radical formation correlates with lipid peroxidation and cytotoxicity by investigating whether the presence of spin traps reduce the cytotoxic effects. A third aim is to identify radioactive oxidation products that remain associated with the U937 cells following exposure to oxidative stress. A fourth aim is to determine the extent to which radioactive PUFA oxidation products can be incorporated into U937 cells. Model compounds that are presently available in radioactive form will be tested; these include hydroxyeicosatetraenoic acids, hydroxyoctadecadienoic acids, and epoxyeicosatrienoic acids. The mechanism of any antiproliferative action will be explored, beginning with possible effects on calcium flux, eicosanoid formation, and cyclic nucleotide formation. In the fifth aim, the antitoxicant enzyme and alpha-tocopherol responses of U937 cells to accumulation of these PUFA oxidation products will be explored. Finally, to test the generality of the findings, potentially important observations made with the U937 cells will be explored in other tumor lines, including the MCF-7 breast carcinoma. This information will provide a better understanding of the role of lipid peroxidation in the cytotoxic effects of anticancer treatments that are associated with free radical generation.

该项目基于氧化脂肪酸的假设。 脂质过氧化导致形成的产品有助于 某些抗癌疗法的总体细胞毒性作用。 总体 目标是识别“稳定”脂质过氧化产物 在暴露于氧化应激的完整肿瘤细胞中形成， 研究这些细胞如何应对的积累 多不饱和脂肪酸（PUFA）过氧化产物，并确定 这些产品的保留是否有助于细胞毒性作用 诱导脂质过氧化的疗法。 主要实验模型将是U937人类单核细胞性白血病 细胞系。 第一个目的是确定由 U937细胞充满PUFA。 接下来，我们将确定是否脂 自由基形成与脂质的过氧化和细胞毒性相关 研究自旋陷阱的存在是否减少了细胞毒性 效果。 第三个目的是识别放射性氧化产物 暴露于氧化后，保持与U937细胞相关联 压力。 第四个目标是确定放射性的程度 PUFA氧化产物可以掺入U937细胞中。 模型 目前以放射性形式可用的化合物将是 测试；这些包括羟基乙烯烯酸， 羟基二糖酸和环氧钠酸。 这 将探索任何抗增殖作用的机制 对钙通量，类类形成和环状有可能影响 核苷酸形成。 在第五目标中，抗毒性酶和 U937细胞对这些PUFA积累的α-生育酚反应 将探索氧化产物。 最后，测试一般性 这些发现，可能是用U937细胞做出的潜在重要观察结果 将在其他肿瘤系中进行探索，包括MCF-7乳房 癌。 这些信息将更好地理解脂质的作用 抗癌治疗的细胞毒性作用的过氧化是 与自由基一代相关。