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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA044530-08S2
Application #
2091505
Study Section
Special Emphasis Panel (SRC (J1))
Project Start
1987-05-01
Project End
1995-12-31
Budget Start
1994-05-23
Budget End
1995-12-31
Support Year
8
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
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
Dinkova-Kostova, A T (2002) Protection against cancer by plant phenylpropenoids: induction of mammalian anticarcinogenic enzymes. Mini Rev Med Chem 2:595-610
Posner, Gary H; Halford, Bethany A; Peleg, Sara et al. (2002) Conceptually new low-calcemic oxime analogues of the hormone 1 alpha,25-dihydroxyvitamin D(3): synthesis and biological testing. J Med Chem 45:1723-30
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

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