These studies seek to elucidate the role of polyamine biosynthesis in: (1) intestinal and colon epithelial cell growth and differentiation; (2) neoplastic transformation of colonic epithelial cells; and (3) the chemotherapy prophylaxis and chemotherapy of human colon polyps and colon cancer. Colon cancer is the leading cause of death due to malignancy in men and women combined, and currently the exact pathogenesis of colon cancer remains unknown. Our studies will probe the role of increased polyamine biosynthesis in the neoplastic transformation process of investigating: (1) relationships between polyamine biosynthesis and DNA replication in normal intestinal epithelial cells induced to proliferate and differentiate by the processes of maturation, regeneration, and adaptive hyperplasia; (2) changes in polyamine biosynthesis which accompany, in a rat model of carcinogen-induced colon cancers, the different stages of neoplastic evolution; and (3) polyamine biosynthetic activity in the colonic epithelium of patients and at-risk family members in kindreds with familial colonic polyposis, including the different stages of development of polyps and subsequent progression to colon cancer. In all of our studies, we will probe the functional role of polyamine biosynthesis for each biologic process by selectively inhibiting the first enzymatic synthesis step in the pathway with alpha difluoromethylornithine (DFMO). This maneuver may have therapeutic implications for altering the course of polyp development and/or treating colon cancer. (S)
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