EXPERIMENTAL BLADDER TUMORS

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.