EFFECTS OF FATTY ACID OXIDATION PRODUCTS ON NEOPLASTIC CELLS

这个项目是基于这样一个假设，即氧化脂肪酸 由于脂质过氧化作用而形成的产物有助于 某些抗癌疗法的总体细胞毒性作用。 整体 目的是确定“稳定的”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 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 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 第一个目的是确定自由基加合物形成的 用PUFA富集的U937细胞。 接下来，我们将确定脂质是否 自由基形成与脂质过氧化和细胞毒性相关， 研究自旋陷阱的存在是否降低了细胞毒性， 方面的影响. 第三个目标是鉴定放射性氧化产物， 在暴露于氧化剂后仍然与U937细胞结合 应力 第四个目标是确定放射性物质 PUFA氧化产物可掺入U937细胞中。 模型 目前以放射性形式可用的化合物将被 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。 的 将探索任何抗增殖作用的机制，从 可能影响钙通量、类二十烷酸的形成和循环 核苷酸形成。 在第五个目标中，解毒酶和 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，为了检验 这些发现，对U937细胞的潜在重要观察， 将在其他肿瘤细胞系中进行探索，包括MCF-7乳腺癌 carcinoma. 这些信息将有助于更好地了解脂质的作用， 过氧化作用的抗癌治疗的细胞毒性作用， 与自由基的产生有关。

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.