FECAPENTAENES MECHANISTIC STUDIES

我们的目的是要深入了解 五烯类和哺乳动物系统中的解毒过程。通过 这种知识、阻止行动和/或加速 这些化合物的失活可能会被现实地探索到最终 降低男性患结肠癌的风险。实现这些目标最好的办法是 结合我们在合成有机化学和结构方面的经验 解释，在分析生物化学和生化药理学，和 在癌症生物学和生物化学方面。 菲五烯及其衍生物将在未标记的和 用稳定的和放射性的同位素标记的。未标记的化合物将是 用于诱变和致癌活性的初步分析 大鼠组织制剂(肝、小肠、 和大肠)。将通过检测以下两种方法监测戒毒情况 致突变性和致癌性的丧失以及通过使用 液体色谱学。稳定的放射性同位素标记 肥五烯将用于机械学研究和鉴定 代谢物。致癌物的两种可能的作用机制是 DNA加合物的形成和原癌基因的激活 哺乳动物细胞。

Our purpose is to pursue an understanding of the mechanism of action of the fecapentaenes and of the detoxication processes in mammalian systems. By such knowledge, the means of blocking the action and/or of accelerating the inactivation of these compounds may be realistically explored to ultimately reduce the risk of colon cancer in man. These goals can be best pursued by combining our experiences in synthetic organic chemistry and structure elucidation, in analytical biochemistry and biochemical pharmacology, and in cancer biology and biochemistry. Fecapentaenes and their derivatives will be synthesized both unlabeled and labeled with stable and radioactive isotopes. Unlabeled compounds will be employed in initial assays of mutagenic and carcinogenic activities and studies of detoxication by rat tissue preparations (liver, small intestine, and large intestine). Detoxication will be monitored both by assays for loss of mutagenicity and carcinogenicity and by chemical analyses using liquid chromatography. Stable and radioactive isotopically labeled fecapentaenes will be used in mechanistic studies and to identify metabolites. Two possible mechanisms of action of carcinogens will be examined: DNA-adduct formation and activation of proto-oncogenes in mammalian cells.