A reliable, highly reproducible model of bladder cancer in Fischer rats using the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) was developed. The natural history and the reversibility or irreversibility of early lesions were determined. It was also demonstrated that the carcinogenic process could be divided into 2-stages with properties similar to the classical murine skin carcinogenesis model of initiation and promotion. FANFT fed for 6 weeks was used as initiator and sodium saccharin and DL-tryptophan demonstrated promoting properties in this model. We propose to evaluate this model with regard to other criteria for initiation and promotion in urinary bladder carcinogenesis including irreversibility of initiation, reversal of order of administration of initiator and promoter, and length of time that promotion administration is required. The possible co-carcinogenicity of sodium saccharin and L-tryptophan will be evaluated. Mechanisms involved in initiation and promotion will be evaluated. Induction of bladder epithelial proliferation appears to be a prerequisite for initiation. Moreover, increasing the level of cell proliferation enhances the effectiveness of a given dose of initiator. Attempts will be made using increased proliferation to develop a model requiring a single dose of orally administered initiator. The anti-promoting activity of 13-cis-retinoic acid will be evaluated. A marker of abnormal cell proliferation in this model is the appearance of pleomorphic microvilli on cell surfaces as detected by scanning electron microscopy. Development of a short term assay for evaluating chemicals for activity toward the bladder will be attempted using pleomorphic microvilli as a marker. Identification of other markers, particularly histochemical assays for use in evaluating the carcinogenic and differentiation process in the bladder, will be attempted.
