The human urinary bladder is an organ in which there is clear epidemiological evidence showing that exposure to environmental chemicals plays a significant etiololgical role in carcinogenesis. For this reason, the development of an in vitro model system to study chemical transformation of human urothelial cells has particular significance and relevance. The primary objective of this project is to perform quantitative studies of cytotoxicity and transformation using cultured normal human transitional epithelial cells. This project is possible because we have developed methods for routinely culturing normal human transitional cells and for quantitatively determining cytotoxicity in these cultures. In addition, we have identified morphological markers in vitro for cultured human transitional carcinoma cells which are potentially useful for transformation assays in vitro. The industrial chemicals 2-napthylamine, 4-aminobiphenyl, and 2-nitrobiphenyl (all human bladder carcinogens requiring metabolic activation), as well as the direct acting carcinogen, N-methyl-N-nitrosourea, will be used in these experiments. Markers used to score transformation will include morphological alterations, growth in soft agar, formation of permanent cell lines, and tumorigenicity in nude mice. The ability of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), and the dietary supplement, sodium saccharin to act as promoters in two stage carcinogenesis of human urothelial cells will be evaluated.
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