Evaluation of Uracil, Sodium Ascorbate, and Rosiglitazone as Promoters of Urinary Bladder Transitional Cell Carcinomas in Male Sprague-Dawley Rats. (February 2018)

• Record Type: Journal Article
• 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
• Is Part Of: Toxicologic pathology. Volume 46:Number 2(2018)
• Page Start: 147
• Page End: 157
• Publication Date: 2018-02
• Subjects: N-butyl-N-(4-hydroxybutyl)-nitrosamine -- rosiglitazone -- sodium ascorbate -- transitional cell carcinomas -- tumor promoters -- uracil -- urinary bladder tumors; Pathology -- Periodicals; Toxicology -- Periodicals; Pathology; Toxicology; 615.9
• DOI: 10.1177/0192623318756004
• Languages: English
• ISSNs: 0192-6233

Abstract

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 sodiuml -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.