The long-term objectives of this program project are to develop methods for lowering the incidence of human malignancy by chemoprotection, i.e., reducing susceptibility to the neoplastic effects of carcinogens. The strategy involves targeting and intercepting the reactive intermediates generated at successive stages (initiation, promotion, progression) of neoplasia. Studies in the Talalay (Project A ) laboratory are based on the well-established principle that induction of detoxication (Phase 2) enzymes is a major mechanism for chemoprotection. The molecular details whereby chemoprotectors (which contain or acquire electrophilic centers) signal the enhanced transcription of Phase 2 enzymes will be elucidated. This project will also continue the development of animal and cell systems for the short-term evaluation of chemoprotectors and elucidation of their mechanisms of action. G.H. Posner's studies (Project B) will clarify the detailed relation between structure of chemoprotective Michael reaction acceptors and their inducer activity by a systematic program of synthesis designed to elucidate the importance of structural, electronic, steric, and hydrophobic factors. Another approach to relating structure and chemoprotective inducer activity is the isolation and structural characterization of inducers from natural (e.g. vegetable) sources. T.W. Kensler (Project C) aims to clarify the role and identity of free radicals involved in tumor promotion and/or progression and to devise strategies using antioxidants to inhibit the formation and/or quench these reactive species. The studies of G.B. Gordon (Project D) will determine the role played by the endogenous steroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) in human disease by measuring serum DHEA and DHEAS levels in relation to the presence or risk of cancer and atherosclerosis. This project will also clarify the mechanism of the antiproliferative and antidifferentiational effects of DHEA in vitro, especially with respect to the importance of the uncompetitive inhibition of glucose-6-phosphate dehydrogenase by DHEA. This integrated research program will therefore utilize chemical, biochemical, molecular and biological approaches to identify targets for chemoprotection, to identify chemoprotectors and their mechanism of action, and to develop novel strategies for chemoprotection.
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