This program-project grant seeks an enhanced understanding of the nature of the carcinogenic processes induced by chemicals. Three of the projects are directed primarily toward a better understanding of the events related to the initiation of neoplasms by chemicals and the other two will provide a better understanding of the post-initiation stages of carcinogenesis. The studies in Dr. Miller's laboratory are directed particularly toward the identification of the electrophilic metabolites of chemical carcinogens that are of major importance to specific carcinogenic processes and to the characterization of the reaction products of these metabolites with cellular macromolecules, especially DNA. Dr. Kasper's studies will provide a better mechanistic understanding of the structures of specific cytochromes P-450, NADPH- cytochrome P-450 oxidoreductase, and epoxide hydrolase as well as of the regulation of their expression in vivo at both the transcriptional and translational levels. These data are of great importance in our understanding of chemical carcinogenesis in view of the involvement of these enzymes in the activation and/or deactivation of a wide variety of chemical carcinogens. Dr. Fahl's research seeks a detailed understanding of the role of glutathione S-transferase-catalyzed reactions in reducing the effective levels of electrophiles formed from carcinogens in target cells and thereby in decreasing the susceptibility of the cells to mutagenesis or carcinogenesis. A study of the potential application of his basic investigations to a specific mutation found in humans may provide an important direct link in our understanding of chemical carcinogenesis in humans. Dr. Drinkwater is exploring genetic factors that predispose mice to the development of macroscopic hepatomas through enhancing the rate of growth of microscopic altered hepatic foci and/or hepatomas. His research is specifically directed toward the characterization of the Hcs gene, which he has shown to be most likely responsible for this predisposition of specific mouse strains to liver cancer and the identification of additional cancer susceptibility genes. Dr. Pitot's research is directed toward an understanding of the molecular and cell alterations critical to the development of malignant neoplasia in the stage of progression during rat hepatocarcinogenesis. These characteristics will be studied during chemically induced multi- stage hepatocarcinogenesis as well as genetically programmed hepatocarcinogenesis in transgenic rats. In order to understand the molecular basis for alterations in genetic expression seen during this and earlier stages in hepatocarcinogenesis, his group will study the regulation of the expression of several specific genes, the regulation of which is altered during carcinogenesis and in malignant neoplasia. This integrated research program will utilize chemical, biochemical, molecular biologic, and biological approaches to develop a better understanding of processes involved in the chemical induction of cancer in mammals.
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