Tumor promotion, a stage of carcinogenesis involving the selection and clonal expansion of precancerous cells, affords the most accessible and practical targets for chemoprotective interventions. It is the goal of this project ot elucidate the role that reactive intermediates, including both free radical species and electrophiles, play in the tumor promotion process. Strategies to inhibit the formation, biomolecular interactions and molecular sequelae of these reactive intermediates with antioxidants, thiols and other scavengers should provide powerful approaches to inhibit the later stages of multistage carcinogenesis. Successful implementation of these approaches will entail the identification of the critical molecular targets of these reactive intermediates and an assessment of the role that modification of these targets play in tumor promotion and progression.
Aim 1 is designed to probe the role of free radicals in tumor promotion/progression in mouse skin using benzoyl peroxide as a model compound. The free radical-dependent, DNA damaging effects (strand breakage and modified bases) will be assessed in mouse skin in vivo using immunofluorescence and HPLC-electrochemical detection assays. Free radical trapping agents and compounds that act to elevate intracellular thiol levels will be evaluated as potential antagonists of these processes. Since free radicals and other reactive intermediates act as weak mitogens, tumor promotion by these classes of agents should be blocked by inhibitors of cell growth. Therefore, Aim 2 is designed to address whether a novel class of potent polyamine analogs can inhibit the tumor promoting actions of radical and electrophile generating tumor promoters. These spermine analogs are powerful inducers of polyamine degradation which, in turn, leads to inhibition of cell growth. Collectively, these studies should provide new insights in the development of mechanism-based chemoprotective strategies.
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