Evaluation of Uracil, Sodium Ascorbate, and Rosiglitazone as Promoters of Urinary Bladder Transitional Cell Carcinomas in Male Sprague-Dawley Rats

• Published in: Toxicologic pathology 2018-02, Vol.46 (2), p.147-157
• Main Authors: Tirmenstein, Mark, Janovitz, Evan, Dorr, Thomas, Song, Yunling, Chen, Shen-Jue, Granaldi, Karen, Chadwick, Kristina D., Mangipudy, Raja, Graziano, Michael, Attalla, Bassem, Haile, Solomon, Czajkowski, Melissa, Foster, John R., Bergholm, Ann-Marie, Billger, Martin, Söderberg, Magnus
• Format: Article
• Language: English
• Subjects: Animals; Ascorbic Acid - toxicity; Carcinogens - pharmacology; Carcinoma, Transitional Cell - chemically induced; Disease Models, Animal; Male; Rats; Rats, Sprague-Dawley; Rosiglitazone - toxicity; Uracil - toxicity; Urinary Bladder - drug effects; Urinary Bladder Neoplasms - chemically induced
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623318756004

The purpose of this study was to establish a 2-stage model of urinary bladder carcinogenesis in male Sprague-Dawley rats to identify tumor promoters. In phase 1 of the study, rats (n = 170) were administered 100 mg/kg of the tumor initiator, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), twice weekly by oral gavage (po) for a period of 6 weeks. Phase 2 consisted of dividing rats into 4 groups (n = 40 per group) and administering one of the following for 26 weeks to identify putative tumor promoters: (1) vehicle po, (2) 25 mg/kg/day rosiglitazone po, (3) 5% dietary sodium l-ascorbate, and (4) 3% dietary uracil. Rats were necropsied after 7.5 months, and urinary bladders were evaluated by histopathology. BBN/vehicle treatments induced the development of urothelial hyperplasia (83%) and papillomas (15%) but no transitional cell carcinomas (TCCs). Rosiglitazone increased the incidence and severity of papillomas (93%) and resulted in TCC in 10% of treated rats. Uracil was the most effective tumor promoter in our study and increased the incidence of papillomas (90%) and TCC (74%). Sodium ascorbate decreased the incidence of urothelial hyperplasia (63%) and did not increase the incidence of urothelial papillomas or TCC. These data confirm the capacity of our 2-stage model to identify urinary bladder tumor promoters.