The objective continues to be the elucidation of the molecular mechanisms of action of chemical carcinogens. This grant will facilitate an interdisciplinary approach, which is required in view of the complexity of the multistage process of carcinogenesis. The proposed studies will follow a logical continuum that includes the following major topics: 1) the chemistry and stereochemistry underlying the covalent binding of chemical carcinogens to DNA, 2) elucidation of the changes in DNA conformation that result from these chemical modifications, as well as studies on their functional significance, 3) the development of highly specific and sensitive immunoassays to facilitate molecular studies on chemical carcinogenesis and 4) molecular genetic studies designed to assess the possibility that the structural changes produced in DNA, as a result of modification by chemical carcinogens, can induce, not only point mutations, but also complex genomic effects, including gene amplification, stable alterations in gene expression and gene transposition (Project E). This integrated approach should provide fundamental insights into basic mechanisms of action of chemical carcinogens and thus provide rational approaches to carcinogen detection, risk extrapolation and cancer prevention.
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