Altered regulation of polyamine metabolism may be one of the biochemical features of preneoplastic cells that contributes to their further development toward a malignant phenotype. Understanding how polyamine metabolism is regulated in normal and preneoplastic cells may lead to better ways to prevent or interrupt neoplastic development than are currently available. A key enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC), will be studied in detail: monoclonal antibodies to the enzyme will be used to study the regulation of this protein in vivo and in vitro, especially in normal vs. preneoplastic cells. The molecular mechanisms by which phorbol esters alter ODC regulation will be studied in a variety of systems, including mouse epidermis in vivo. Differences in several aspects of the regulation of polyamine metabolism between hamster fibroblasts and epidermal cells will be defined and characterized in detail. The ability of tumor-promoting phorbol esters (compounds known to perturb polyamine metabolism in many cell types as well as promote tumors in epithelia in vivo) to rescue carcinogen-altered primary epidermal cells from a program of terminal differentiation will be studied. The goals of these studies are to understand how polyamine metabolism is regulated in normal cells, and how this regulation is affected by tumor promoters and neoplastic transformation. Once understood, polyamine metabolism may be a candidate for the rational design of drugs to interfere with further progression of preneoplastic and neoplastic cells in vivo.
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