The overall objective of the proposed research program is to provide new information that will increase our understanding of cancer causation and provides new approaches for the prevention of cancer. The proposed research is concerned with: (1) identification of ultimate mutagenic and carcinogenic metabolites of polycyclic aromatic hydrocarbons and related nitrogen-containing heterocyclic hydrocarbons 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 environmentally important polycyclic aromatic hydrocarbons and their related nitrogen- containing heterocycles. (2) mechanisms of carcinogenesis and mutagenesis by optically active R,S,S,R bay-region diol epoxides of polycyclic aromatic hydrocarbons and their nitrogen-containing analogs. 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 and azapolycyclic aromatic hydrocarbons as probes for identifying cellular targets that are important for mutagenesis and carcinogenesis. We will determine the effects of optically active bay-region diol epoxide enantiomers on DNA base sequences in the coding region of the endogenous hypoxanthine phosphoribosyltransferase (HPRT) gene of Chinese hamster V-79 cells. We will also evaluate the mechanisms and possible in vivo significance of our recent observation of dose-dependent differences in the profile of mutations for an R,S,S,R bay-region diol epoxide in V-79 cells. We will determine whether the kinds of mutations that occur in the p53 and ras genes in tumors from animals the receive a high dose of the diol epoxide are the same or different from the mutations that occur in tumors from animals that receive a low dose of the carcinogen. An important goal of our research is to compare the mutation profiles of optically pure R,S,S,R bay-region diol epoxides in V-79 cells in vitro with the mutation profiles of these compounds in vivo. (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 athe carcinogenic process. We will evaluate (a) potential inhibitory effects of curcumin, carnosol, ursolic acid, rosemary, tea and other dietary plant substances on chemical carcinogenesis and ultraviolet light-induced carcinogenesis, (b) potential inhibitory and/or stimulatory effects of 1alpha, 25-dihydroxyvitamin D3 on chemical carcinogenesis and ultraviolet light-induced carcinogenesis and (c) effects of chemopreventive substances on the growth and progression of skin papillomas. Possible mechanisms of action will be evaluated.
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