The long-term objectives are to devise rational chemical and dietary strategies for reducing susceptibility to carcinogens (chemoprotection) thereby lowering the risk of cancer. The strategies involve targeting and intercepting the reactive DNA-damaging intermediates generated at successive stages of neoplasia (initiation, promotion, progression).; pinpointing new targets for chemoprotective intervention; identifying new chemoprotective chemicals and edible plants rich in such activities; and developing short-term markers for assessing chemoprotection in humans. The central theme of Project No. 1 (P.Talalay) is that induction of Phase 2 detoxication enzymes is a major mechanism for achieving chemoprotection. This strategy is to be implemented by developing edible cruciferous plants rich in inducer activity and characterizing their inducers chemically. Most of the inducer activity in these plants appears to associated with isothiocyanates and their glucosinolate precursors. The molecular mechanisms whereby structurally diverse protectors (most of which contain electrophilic centers) enhance the transcription of genes encoding for Phase 2 enzymes will be elucidated. The goals of Project No.2 (T.A Shapiro) are to devise noninvasive methods for evaluating the effectiveness of these high inducer content plants in raising the overall Phase 2 enzyme functional capacity in humans. The capacity of humans to degrade glucosinolates to isothiocyanates will also be measured. In Project No.3 (T.W. Kensler) reactive intermediates (free radicals and electrophiles) rising from tumor promoters and their targets will be identified; their role in later stages of carcinogenesis elucidated; and chemoprotection by interception of these reactive intermediates by thiol reagents and polyamine analogs will be attempted. In Project No. 4 (G.H. Posner) novel vitamin D3 analogs with enhanced antiproliferative and differentiational and low calcemic activities will be designed and synthesized, and their biological activities evaluated in cell and animal systems. Core A (G.H. Posner) is a facility for chemical structure elucidation and large-scale synthesis serving Projects No. 1 and No. 3. Core B (P. Talalay) will coordinate fiscal, administrative and common services. This integrated program will therefore utilize chemical, biochemical, molecular and tumor biology approaches to uncover new targets for chemoprotection, to identify chemoprotectors, to evaluate them in subcellular and cellular systems and in animals, to elucidate their mechanisms of action, and to devise methods for assessing chemoprotection in humans.
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