Production of urothelial tumors in the heterotopic bladder of rats by instillation of N-glucuronosyl or N-acetyl derivatives of N-hydroxy-2-aminofluorene.

Male F344 rats which had been implanted with a heterotopic bladder were randomly divided into four groups and their heterotopic bladders were instilled once a week for 30 weeks with 0.5 ml phosphate-buffered saline-dimethyl sulfoxide solution (4:1), or this solution containing 2 mumol N-methyl-N-nitrosourea, 1 mumol N-hydroxy-2-acetylaminofluorene (N-OH-AAF), or 1 mumol N-hydroxy-N-glucuronosyl-2-aminofluorene (N-OH-N-Gl-AF). These bladders were then instilled once a week for an additional 23 weeks with phosphate buffered saline solution without the addition of dimethyl sulfoxide. The animals were killed at the end of 53 weeks. Transitional cell carcinomas were observed in five of 37, 36 of 37, 15 of 35, and 36 of 38 rats of the control, N-methyl-N-nitrosourea, N-OH-AAF, and N-OH-N-Gl-AF groups, respectively. No histological alteration was observed in their natural bladders and no tumor was observed in the liver. As judged by kinetic measurements of the radioactive compounds, N-OH-AAF was removed much faster than N-OH-N-Gl-AF from the fluid of heterotopic bladder. The pH of the fluid in the bladder was between 7.1 and 7.4. The present study demonstrates the carcinogenicity of N-OH-N-Gl-AF and N-OH-AAF for rat bladder.