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.
| Cho, Hye-Youn; Reddy, Sekhar P; Debiase, Andrea et al. (2005) Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radic Biol Med 38:325-43 |
| Guyton, Kathryn Z; Kensler, Thomas W; Posner, Gary H (2003) Vitamin D and vitamin D analogs as cancer chemopreventive agents. Nutr Rev 61:227-38 |
| Peleg, Sara; Posner, Gary H (2003) Vitamin D analogs as modulators of vitamin D receptor action. Curr Top Med Chem 3:1555-72 |
| Cho, Hye-Youn; Jedlicka, Anne E; Reddy, Sekhar P M et al. (2002) Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 26:175-82 |
| Cho, Hye-Youn; Jedlicka, Anne E; Reddy, Sekhar P M et al. (2002) Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Am J Respir Cell Mol Biol 26:42-51 |
| Posner, Gary H; Northrop, John; Paik, Ik-Hyeon et al. (2002) New chemical and biological aspects of artemisinin-derived trioxane dimers. Bioorg Med Chem 10:227-32 |
| Pereira, Fernanda Maria Valente; Rosa, Eduardo; Fahey, Jed W et al. (2002) Influence of temperature and ontogeny on the levels of glucosinolates in broccoli (Brassica oleracea Var. italica) sprouts and their effect on the induction of mammalian phase 2 enzymes. J Agric Food Chem 50:6239-44 |
| Ye, Lingxiang; Dinkova-Kostova, Albena T; Wade, Kristina L et al. (2002) Quantitative determination of dithiocarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans. Clin Chim Acta 316:43-53 |
| Posner, Gary H; Woodard, Benjamin T; Crawford, Kenneth R et al. (2002) 2,2-Disubstituted analogues of the natural hormone 1 alpha,25-dihydroxyvitamin D(3): chemistry and biology. Bioorg Med Chem 10:2353-65 |
| Kensler, Thomas W; Egner, Patricia A; Wang, Jin-Bing et al. (2002) Strategies for chemoprevention of liver cancer. Eur J Cancer Prev 11 Suppl 2:S58-64 |
Showing the most recent 10 out of 122 publications
