Urinary bladder carcinogenesis with N-substituted aryl compounds: initiation and promotion

Aromatic amines have been implicated in the etiology of bladder cancer in humans since Rehn observed the disease in 3 workers in the German aniline dye industry in 1895. 2-Naphthylamine was identified 40 years later as one of the carcinogens in tests involving the feeding of the chemical to dogs. The discovery of N-2-fluorenylacetamide as a carcinogen in rodents inducing tumors of the bladder and other organs provided a more inexpensive and rapid model for the study of bladder carcinogenesis. The metabolic activation pathways of aromatic amine and amide compounds has been extensively examined. In the 1960's, organ-specific rodent models were discovered with the use of N-butyl-N-(4-hydroxybutyl) nitrosamine, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, or N-methyl-N-nitrosourea. Recent experiments have demonstrated that bladder carcinogenesis can be divided into two stages similar to the initiation-promotion model in mouse skin. Possible promoters have included sodium saccharin, sodium cyclamate, and tryptophan. Certain metabolites of the latter compound are also N-substituted aryl compounds. Lastly, recent studies of the relationship of urine to the carcinogenic process in the bladder indicate that it can act as a promoting agent as well as a carrier of carcinogenic substances.