The primary objective of this proposal is to identify analogs of ellagic acid (EA), a naturally occurring plant phenol, that would be effective as inhibitors of N-nitrosamine carcinogenesis in the rat esophagus. Although EA has been shown to inhibit polycyclic aromatic hydrocarbon tumorigenesis in other laboratories, and N- nitrosobenzylmethylamine-induced esophageal tumors in rats in our laboratory, it is poorly absorbed by tissues and induces systemic toxicity following parenteral injection. Therefore, we propose to synthesize analogs of EA that are more lipophilic and/or nucleophilic than EA, and screen these analogs for anti-mutagenic potential in Chinese hamster V-79 cells, bioavailability, toxicity in vivo, and for their effects on metabolism of N-nitrosamines in cultured esophageal tissues. These studies should lead to the identification of one or more analog(s) with significant anticarcinogenic potential, which would then be evaluated for their ability to inhibit N-nitrosamine induced esophageal tumors in rats when administered in the diet. In addition, the analogs will be tested for their ability to inhibit N-nitrosamine-induced liver tumors in F344 rats when administered in the diet. This will provide an assessment of the inhibitory potential of the analogs in organs that are distant from the site of absorption of the analog(s). Since there are very few known inhibitors of esophageal carcinogenesis in vivo, it is anticipated that these studies will permit the identification of compound(s) that could be used in chemoprevention trials of esophageal cancer in human populations.
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