Certain chronic inflammatory conditions are associated with an increased risk for the development of cancer (e.g. ulcerative colitis) and chronic inflammation may be important for the promotion of many other types of tumors. Previously, we have shown that stimulated human phagcoytes induce mutations in bacteria and cytogenetic damage in cultured mammalian cells by a process mediated by phagocyte-generatd toxic oxygen metabolites (superoxide, hydrogen peroxide, hydroxyl radicals). The goals of this project will be to: (1) evaluate further the cytogenetic effects of phagocyte-generated toxic oxygen metabolites on cultured mammalian cells; (2) evaluate the effects of inhibitors of toxix oxygen metabolites (e.g. oxygen radical scavengers, antioxidants) in these same mammalian systems; (3) determine whether stimulated human phagocytes produce cytogenetic damage in vivo. The assays to evaluate cytogenetic damage are: (1) the sister chromatid exchange assay, (2) mutation at the HGPRT locus in Chinese Hamster Ovary cells, (3) the malignant transformation assay using C3H mouse embryo cells, (4) an in vivo transformation assay using athymic BALB/c nude mice and (5) the hamster buccal pouch system to study the effects of stimulated phagocytes on normal epithelium in vivo. Because chronic inflammation is associated with many types of cancer, phagocytes may play an important role in the neoplastic process. This project is designed to study the pathogenesis of that relationship and methods by which the process of phagocyte-induced carcinogenesis can be modulated or inhibited.
