Human urinary bladder cancer is associated with exposure to chemical carcinogens, and several experimental rodent models are available which closely mimic the disease. These models involve administration of genotoxic chemicals, such as N-[4-5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), or non-genotoxic chemicals, such as uracil or sodium saccharin (NaSac). Increased cell proliferation of the urothelium is a major factor which affects the tumor dose-response of genotoxic chemicals and has a primary role in nongenotoxic chemical carcinogenesis. The ultimate consequence of either group of chemicals is generation of errors in specific genes (oncogenes and suppressor genes) which lead to the development of cancer. Mutations in the ras family of genes have been demonstrated following FANFT treatment, and more recently we have demonstrated that mutations occur in the gene for p53. We plan to further evaluate mutations in p53 during different stages of bladder carcinogenesis, comparing the changes during administration of genotoxic (FANFT and BBN) or nongenotoxic (uracil and NaSac) carcinogens. It has been hypothesized that tumors arising secondary to treatment with nongenotoxic agents more frequently involve mutations in CpG islands than is the case for tumors arising from treatment with genotoxic agents, even though ultimately, the same genes are affected. The spectrum of mutations will be compared in the above models. NaSac is a nongenotoxic carcinogen in rats, with males more susceptible than females, but bladder cancer occurs only if NaSac is administered beginning at birth and continuing for the life of the animal. Increased cell proliferation is a key factor by which NaSac acts, and this appears to occur secondary to toxicity caused by the formation of silicate- containing precipitate and/or crystals following treatment with high doses of NaSac. The role of these silicates in saccharin carcinogenesis will be investigated including the role of dose, comparison with other sodium salts and their related acids, other classes of bladder tumor promoters, and comparison of rat strains and other species. The mechanism by which these precipitates and/or crystals form in the urine and the multiple factors by which influence their formation will be studied. By testing this hypothesis further, a more rational basis for extrapolation of the findings in rats to a possible risk for humans can be made.
