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: 6237520
• 负责人: ARTHUR A. SPECTOR
• 金额: $ 15.64万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 1998-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237520
• 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.

本课题是基于氧化脂肪酸的假设