EFFECTS OF FATTY ACID OXIDATION PRODUCTS ON NEOPLASTIC CELLS

这个项目是基于这样一种假设：氧化脂肪酸 由于脂质过氧化而形成的产物有助于 某些抗癌治疗的整体细胞毒性效应。整体而言 目的是鉴定稳定的脂质过氧化产物 在暴露在氧化应激下的完整肿瘤细胞中形成， 研究这些细胞如何应对积聚的 多不饱和脂肪酸(PUFA)过氧化产物，并测定 这些产品的保留是否有助于细胞毒性作用 导致脂质过氧化的治疗方法。 主要的实验模型将是U937人单核细胞白血病 细胞系。第一个目标是鉴定由形成的自由基加合物 富含多不饱和脂肪酸的U937细胞。接下来，我们将确定脂质是否 自由基的形成与脂质过氧化和细胞毒性有关 研究自旋陷阱的存在是否降低了细胞毒性 效果。第三个目标是识别放射性氧化产物， 暴露于氧化环境后仍与U937细胞有关 压力。第四个目标是确定辐射的程度 多不饱和脂肪酸氧化产物可被掺入U937细胞。型号 目前以放射性形式存在的化合物将是 测试；这些包括羟基二十碳四烯酸， 羟基十八碳二烯酸和环氧二十碳三烯酸。这个 任何抗增殖作用的机制都将被探索，从 可能对钙流、二十烷类化合物的形成和循环产生影响 核苷酸形成。在第五个目标中，抗毒酶和 U937细胞对这些多不饱和脂肪酸蓄积的α-生育酚反应 将探索氧化产物。最后，为了测试的通用性 这些发现是对U937细胞进行的潜在重要观察 将在包括MCF-7乳腺在内的其他肿瘤系中进行探索 癌症。 这些信息将有助于更好地理解脂质的作用 抗癌治疗的细胞毒作用中的过氧化作用 与自由基生成有关。

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.