BIOCHEMICAL STUDIES IN CHEMICAL CARCINOGENESIS

  • Farnham, Peggy, (PI)
  • Boutwell, Roswell (PI)
  • Miller, Elizabeth (PI)
  • Pitot, Henry (PI)
  • Sandgren, Eric (PI)
  • Bradfield, Christopher (PI)
  • Pitot, Henry (PI)
  • Drinkwater, Norman R. (PI)
  • Pitot, Henry (PI)
  • Miller, James (PI)
  • Drinkwater, Norman (PI)
  • Kasper, Charles (PI)
  • Fahl, William (PI)

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date4/1/783/31/12

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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