The overall objective of the proposed research program is to provide new information that will increase our understanding of cancer causation and provide new approaches for the prevention of cancer. The proposed research is concerned with: (1) identification of proximate and ultimate mutagenic and carcinogenic metabolites of polycyclic aromatic hydrocarbons and related nitrogen- containing heterocyclic compounds in our environment. An important aim of this research is to enhance our understanding of poorly explored aspects of structure-activity relationships of diol epoxides from polycyclic aromatic hydrocarbons and nitrogen-containing heterocytes. (2) mechanisms of carcinogenesis and mutagenesis by optically active R, S, S, R bay-region diol epoxides of polycyclic aromatic hydrocarbons and nitrogen-containing heterocycles. In this research, we will use R, S, S, R bay-region diol epoxides (ultimate mutagens and carcinogens) and their closely related optically active but biologically less active or inactive S, R, R, S enantiomers from several polycyclic aromatic hydrocarbons and nitrogen-containing heterocycles as probes for identifying cellular targets that are important for mutagenesis. We will determine (a) the effect of optically active bay-region diol epoxide enantiomers on DNA base sequences in the coding region of the endogenous hypoxanthine phosphoribosyltransferase gene of Chinese hamster V-79 cells and (b) effects of optically active bay-region diol epoxide enantiomers on the fidelity of DNA polymerase (a) possible protein target for ultimate carcinogens). (3) inhibitory effects of naturally occurring dietary constituents and their derivatives on chemical carcinogenesis and ultraviolet light-induced carcinogenesis. In this research, we will attempt to identify potentially useful inhibitors of carcinogenesis and to use these inhibitors as tools for better understanding of the carcinogenic process. We will evaluate (a) potential antagonists of bay-region diol epoxides of polycyclic aromatic hydrocarbons. (b) potential inhibitory effects of curcumin, carnosol, rosemary and other dietary plant substances on chemical carcinogenesis and ultraviolet light-induced carcinogenesis and (c) potential inhibitory and/or stimulatory effects of vitamin D3, 1alpha,25-dihydroxyvitamin D3 and calcium on chemical carcinogenesis and ultraviolet light-induced carcinogenesis. Possible mechanisms of action will be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA049756-02
Application #
3479754
Study Section
Special Emphasis Panel (SRC (N2))
Project Start
1990-08-01
Project End
1997-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Rutgers University
Department
Type
Schools of Pharmacy
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Conney, Allan H; Lou, You-Rong; Nghiem, Paul et al. (2013) Inhibition of UVB-induced nonmelanoma skin cancer: a path from tea to caffeine to exercise to decreased tissue fat. Top Curr Chem 329:61-72
Conney, Allan H; Kramata, Pavel; Lou, You-Rong et al. (2008) Effect of caffeine on UVB-induced carcinogenesis, apoptosis, and the elimination of UVB-induced patches of p53 mutant epidermal cells in SKH-1 mice. Photochem Photobiol 84:330-8
Conney, Allan H; Zhou, Sherry; Lee, Mao-Jung et al. (2007) Stimulatory effect of oral administration of tea, coffee or caffeine on UVB-induced apoptosis in the epidermis of SKH-1 mice. Toxicol Appl Pharmacol 224:209-13
Wogan, Gerald N; Hecht, Stephen S; Felton, James S et al. (2004) Environmental and chemical carcinogenesis. Semin Cancer Biol 14:473-86
Conney, Allan H (2004) Tailoring cancer chemoprevention regimens to the individual. J Cell Biochem 91:277-86
Conney, Allan H (2003) Enzyme induction and dietary chemicals as approaches to cancer chemoprevention: the Seventh DeWitt S. Goodman Lecture. Cancer Res 63:7005-31
Conney, A H; Chang, R L; Cui, X X et al. (2001) Dose-dependent differences in the profile of mutations induced by carcinogenic (R,S,S,R) bay- and fjord-region diol epoxides of polycyclic aromatic hydrocarbons. Adv Exp Med Biol 500:697-707
Lu, Y P; Lou, Y R; Lin, Y et al. (2001) Inhibitory effects of orally administered green tea, black tea, and caffeine on skin carcinogenesis in mice previously treated with ultraviolet B light (high-risk mice): relationship to decreased tissue fat. Cancer Res 61:5002-9
Kumar, S; Chang, R L; Wood, A W et al. (2001) Tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle dibenz[a,h]acridine on mouse skin. Carcinogenesis 22:951-5
Zhu, B T; Patel, U K; Cai, M X et al. (2000) O-Methylation of tea polyphenols catalyzed by human placental cytosolic catechol-O-methyltransferase. Drug Metab Dispos 28:1024-30

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