PEROXYL RADICALS, HYDROPEROXIDES, AND CARCINOGENESIS

过氧基自由基和氢过氧化氢很容易从 氧化的有机分子。最近的实验表明，过氧基 自由基和过氧化氢参与了引发和促进 癌症发生的阶段。用于评估的体内定量数据 由于不稳定，这样的假设很难得到 以及过氧基和氢过氧化氢的反应性。此应用程序 概述旨在提供以下基本信息的实验 两种植物体内过氧化自由基和氢过氧化产物的存在及活性 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]芘是一种高度特异的 过氧基的反应陷阱。我们建议将其应用于小鼠皮肤 并对皮肤处理后的氧化产物进行定量 肿瘤促进剂和其他制剂。这应该会提供第一个直接 靶材中产生的过氧化自由基水平的测量 作为药理学挑战的结果的组织。 我们已经证明了脂肪酸氢氧化物和脂肪酸醇 刺激大鼠DNA合成并诱导鸟氨酸二羧酶活性 直肠内滴注后的结肠。这表明，主要的 不饱和脂肪酸的氧化产物有助于 结肠癌发生的启动后阶段。我们提出了几个建议 验证这一假说的实验。类似物将被合成成 准确确定加固的结构要求 上皮细胞增殖。将开发方法来量化 氧化脂肪酸衍生物的水平存在于结肠腔中。 将进行致癌实验以确定 氧化脂肪酸衍生物在结肠中的促肿瘤活性。 这些研究应该提供关于一类新的 不饱和脂肪酸通过过氧基衍生的潜在促癌物质 激进分子。

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.