Promotion in urinary bladder carcinogenesis.

Aromatic amines, including 2-naphthylamine, 4-aminobiphenyl and benzidine, are known urinary bladder carcinogens in man and other species, but in rodents, aromatic amines and amides have usually induced liver tumors, occasionally also with tumors of the bladder and other tissues. Variations in organ specificity are related to differences in metabolism; for the production of bladder tumors, the rates of acetylation and deacetylation appear to be critical. Bladder specific carcinogens in rodents and other species have subsequently been identified, including N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) administered in the drinking water, N-[(4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) in the diet and N-methyl-N-nitrosourea (MNU) instilled intravesically. When low doses of several bladder carcinogens (BBN, FANFT, 2-acetylaminofluorene, and 3,3'-dichlorobenzidine) are administered to rats, either simultaneously or sequentially, a synergistic effect is observed with respect to bladder carcinogenesis. In addition, a multistage carcinogenesis process has been demonstrated for the rat bladder using MNU or FANFT as initiators, and dietary sodium saccharin, sodium cyclamate, or tryptophan as promoters. Calculi (or pellets) appear to enhance the promotion process but are not necessary for it to occur. Recent studies also indicate that urine has a role in the promoting process. The urothelium normally has a very low mitotic rate. If mucosal proliferation is increased, such as during fetal development or during regeneration and repair of an ulcer, the bladder appears to be considerably more sensitive to the effects of promoting substances. For example, if sodium saccharin is administered to rats after ulceration of the bladder, even without prior administration of an initiator, bladder carcinoma develops. Under these conditions, the substance appears as a carcinogen. Human populations with increased bladder epithelial proliferation, such as fetus, infants, patients with bacterial cystitis or men with partially obstructive prostatism, may have increased susceptibility to the action of carcinogenic or promoting stimuli.