PEROXYL RADICALS, HYDROPEROXIDES, AND CARCINOGENESIS

过氧化氢自由基和氢过氧化物很容易形成， 氧化的有机分子 最近的实验表明过氧 自由基和氢过氧化物参与引发和促进 癌发生的阶段。 用于评价的定量体内数据 由于不稳定性，此类假设很难获得 以及过氧自由基和氢过氧化物的反应性。 本申请 概述了旨在提供有关 在两个实验室中过氧自由基和氢过氧化物的存在和活动 不同的动物模型系统。 我们实验室的研究已经证实， （+）-7，8-二羟基-7，8-二氢苯并[a]芘是一种特异性高的 过氧化氢自由基的反应陷阱。 我们建议将其应用于小鼠皮肤 并在用以下物质处理皮肤后定量其氧化产物： 肿瘤促进剂和其它试剂。 这将提供第一个直接 目标中产生的过氧自由基水平的测量 组织作为药理学挑战的结果。 我们已经表明，脂肪酸氢过氧化物和脂肪酸醇 刺激大鼠DNA合成和诱导鸟氨酸二羧化酶活性 直肠内滴注后的结肠。 这表明，主要 不饱和脂肪酸的氧化产物有助于 结肠癌发生的后起始阶段。 我们提出了几 实验来验证这个假设。 将合成类似物， 准确确定结构要求，以提高 上皮增生 将开发方法来定量 结肠腔中存在的氧化脂肪酸衍生物的水平。 将进行致癌实验以确定 氧化脂肪酸衍生物在结肠中的肿瘤促进活性。 这些研究应该提供关于一类新的 不饱和脂肪酸经过氧衍生的潜在肿瘤促进剂 根的

Peroxyl free radicals and hydroperoxides are readily formed from easily oxidized organic molecules. Recent experiments suggest the peroxyl radicals and hydroperoxides are involved in the initiation and promotion phases of carcinogenesis. Quantitative in vivo data with which to evaluate such hypotheses have been difficult to obtain because of the instability and reactivity of peroxyl radicals and hydroperoxides. This application outlines experiments designed to provide fundamental information about the occurrence and activities of peroxyl radicals and hydroperoxides in two different animal model systems. Research from our laboratory has established that (+)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene is a specific and highly reactive trap for peroxyl radicals. We propose to apply it to mouse skin and quantitate its oxidation products after treatment of the skin with tumor promoters and other agents. This should provide the first direct measurements of the levels of peroxyl free radicals generated in target tissues as a result of pharmacological challenge. We have shown that fatty acid hydroperoxides and fatty acid alcohols stimulate DNA synthesis and induce ornithine dicarboxylase activity in rat colon following intrarectal instillation. This suggests that primary oxidation products of unsaturated fatty acids contribute to the post-initiation phase of colon carcinogenesis. We propose several experiments to test this hypothesis. Analogues will be synthesized to determine precisely the structural requirements for enhancement of epithelial proliferation. Methods will be developed to quantitate the levels of oxidized fatty acid derivatives present in the colonic lumen. Carcinogenesis experiments will be performed to determine the tumor-promoting activity of oxidized fatty acid derivatives in the colon. These studies should provide critical information about a novel class of potential tumor promoters derived from unsaturated fatty acids via peroxyl radicals.