FECAPENTAENES MECHANISTIC STUDIES

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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.