Frequent p53 mutations and occasional loss of chromosome 4 in invasive bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in B6D2F1 mice

• Published in: Molecular carcinogenesis Vol. 21; no. 1; pp. 70 - 79
• Main Authors: Ogawa, Kumiko, Uzvolgyi, Éva, St. John, Margaret K., de Oliveira, Maria Luiza, Arnold, Lora, Cohen, Samuel M.
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 01.01.1998
• Subjects: Animals; bladder cancer; Butylhydroxybutylnitrosamine; cancer genetics; Carcinogens; Carcinoma - chemically induced; Carcinoma - genetics; Carcinoma - pathology; Chromosome Deletion; Humans; Male; Mice; Mutation; suppressor genes; Tumor Suppressor Protein p53 - genetics; Uracil - administration & dosage; Uracil - pharmacology; Urinary Bladder Neoplasms - chemically induced; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/(SICI)1098-2744(199801)21:1<70::AID-MC9>3.0.CO;2-T

B6D2F1 mice (45/group) were treated with N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) or uracil as follows: Group 1 received 0.05% BBN in drinking water for the entire experiment, Group 2 received 5 mg of BBN by gastric gavage in 0.1 mL of 20% ethanol twice per week for 10 wk, Group 3 received a 2.5% uracil–containing diet for the entire experiment, and Group 4 was controls (received 0.1 mL of 20% ethanol by gavage twice per week for 10 wk). The surviving mice in Group 1 were killed after week 26 and those in the other groups after week 30. By week 15, three of 11 Group 1 and one of 15 Group 2 mice had bladder carcinoma. By 26 and 30 wk, respectively, invasive carcinomas were observed in 33 of 34 and six of 21 mice in Groups 1 and 2 and renal pelvic carcinomas in 11 of 34 and three of 21 mice in Groups 1 and 2. Four of 19 uracil‐treated mice had bladder nodular hyperplasia. By polymerase chain reaction–single‐strand conformation polymorphism and sequence analyses, 16 of 20 and two of five bladder carcinomas from Groups 1 and 2, respectively, showed mutations in the p53 gene. Ha‐ras mutation was present in one case. Loss of heterozygosity analysis with simple‐sequence length polymorphism markers for chromosome 4 showed that 10 of 21, two of 15, and nine of 13 mice in Groups 1–3, respectively, had heterozygous or homozygous deletions. B6D2F1 mice are therefore susceptible to the urothelial carcinogenic effects of BBN and develop frequent p53 mutations and chromosome 4 deletions. Chromosome 4 deletions were also seen with uracil. Mol. Carcinog. 21:70–79, 1998. © 1998 Wiley‐Liss, Inc.