Squamous cell carcinoma (SCC) of the human esophagus is a multifactorial disease with a significant behavorial component. Primary chemoprevention has emerged as a potentially viable approach to reduce the risk of esophageal cancer in high-risk individuals. N-Nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in the F-344 rat has proven to be a useful animal model for investigations of SCC of the esophagus. For the last fifteen years, the goal of our laboratory has been to identify effective chemopreventive agents for the disease using this animal model. Our previous work (5-10 years ago) with isothiocyanates demonstrated that phenethyl isothiocyanate (PEITC) and 3- phenylpropyl isothiocyanate (PPITC) are exquisitely potent inhibitors of tumor initiation (i.e., blocking agents) in the rat esophagus. However, at that time, there were few, if any, demonstrable inhibitors of the promotion/progression stages of rat esophageal tumorigenesis (i.e., suppressing agents). Thus, the past five years have been largely devoted to the discovery of non-isothiocyanate chemopreventive agents in this model, particularly the identification of potent suppressing agents. We have found that lyophilized black raspberries (BRB) act as an effective chemopreventive agent in the model, and that BRB exhibit both blocking and suppressing activity. Our preliminary data indicate that BRB exhibit blocking activity by influencing the metabolism of NMBA, thus reducing the levels of NMBA-induced damage in esophageal DNA. At least one mechanism by which BRB exhibit suppressing activity is by reducing the growth rate of preneoplastic esophageal epithelial cells. The ultimate goals of the proposed project are to develop an improved understanding of the mechanism(s) by which BRB exhibit blocking and suppressing activity in the rat esophagus and to develop an effective """"""""cocktail"""""""" of chemopreventive agents for later use in the primary chemoprevention of human esophageal SCC. Accordingly, we propose the following Specific Aims for our future investigations: (1) to identify the active inhibitory components of lyophilized BRB; (2) to determine the mechanistic basis of the anti-initiating effects of lyophilized BRB; (3) to investigate the mechanistic basis of the suppressing effects of lyophilized BRB; (4) to test the chemopreventive efficacies of specific compounds isolated from lyophilized BRB or specific BRB extracts; and (5) to evaluate the combined effects of BRB isolates and isothiocyanates on rat esophageal tumorigenesis.
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