Effect of Regenerative Hyperplasia on the Urinary Bladder: Carcinogenicity of Sodium Saccharin and N-[4-(5-Nitro-2- furyl)-2-thiazolyl]formamide1

The effect of ulcérationof the urinary bladder on bladder carcinogenesis induced by W-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or sodium saccharin was evaluated in 5week-old F344 rats which were all killed 2 years after the start of the experiment. The results indicate that long-term feeding of sodium saccharin, a nonmutagen, appears to be capable of inducing bladder tumors if administered to a rat with a prolif erating bladder mucosa even without FANFT "initiation." Ul cérationwas induced by freezing. FANFT was fed at a level of 0.2% of the diet for 2 weeks, and sodium saccharin was fed as 5% of the diet for 102 or 104 weeks. Ulcérationfollowed immediately by FANFT administration and then by control diet for 102 weeks did not result in bladder tumors, whereas FANFT administration followed by ulcérationand then control diet for a similar period induced bladder tumors. Ulcérationfollowed by FANFT administration and then by 102 weeks of sodium saccharin feeding induced bladder tumors, but ulcérationfol lowed by 2 weeks of control diet followed by 102 weeks of sodium saccharin feeding induced a similar incidence of tu mors. Ulcérationfollowed immediately by sodium saccharin (fed for 104 weeks) induced a slightly lower incidence of tumors. FANFT followed by sodium saccharin without ulcéra tion induced a single bladder carcinoma, but either chemical alone did not induce bladder tumors. Ulcérationof the urinary bladder produced by a single i.p. injection of cyclophosphamide (100 mg/kg) gave similar results as ulcérationby freez ing. Ulcérationalone induced by freezing or cyclophosphamide was followed by a reversible, regenerative nodular and papillary hyperplasia, and the bladder mucosa returned to normal in 3 to 4 weeks after ulcérationand remained normal through 2 years. The lack of enhancing effect of FANFT, a potent mutagen, compared to control diet and ulcérationinduced by cyclo phosphamide, a mutagenic alkylating agent, compared to ul cérationinduced by freezing support the hypothesis of carci nogenesis occurring without mutation. These results may also help to explain the carcinogenicity of sodium saccharin in twogeneration and pellet implantation experiments and may assist in the identification of populations with increased susceptibility to bladder cancer. ' This work was supported In part by USPHS Grant CA 15945 from the National Cancer Institute through the National Bladder Cancer Project and by USPHS Grant RR 05660. 2 To whom requests for reprints should be addressed, at Department of Pathology, University of Nebraska Medical Center, 42nd and Dewey Ave., Omaha, Nebr. 68105. 3 Present address: First Department of Pathology, Nagoya City University Medical School, Nagoya 467, Japan. 4 Deputy Director, National Bladder Cancer Project, St. Vincent Hospital. Received May 12, 1981 ; accepted October 12, 198