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High frequency of ras mutations in forestomach and lung tumors of B6C3F1 mice exposed to 1-amino-2,4-dibromoanthraquinone for 2 years.

Abstract
1-Amino-2,4-dibromoanthraquinone (ADBAQ) is an anthraquinone-derived vat dye, and a potent carcinogen in laboratory animals. In a 2-year study with dietary exposure to 10,000 or 20,000 ppm ADBAQ, increased incidence of forestomach and lung tumors were observed in B6C3F1 mice. The present study indentified genetic alterations in H-ras and K-ras proto-oncogenes in ADBAQ-induced tumors. Point mutations in ras proto-oncogenes were identified by restriction fragment length polymorphism, single-stranded conformational polymorphism analysis and cycle sequencing of polymerase chain reaction-amplified DNA isolated from paraffin-embedded squamous cell papillomas and carcinomas in the forestomach, and alveolar/bronchiolar adenomas and carcinomas in the lung. A higher frequency of ras mutations was identified in ADBAQ-induced forestomach (23/32, 72%) and lung tumors (16/23, 70%) than in spontaneous forestomach (4/11, 36%) and lung tumors (26/86, 30%). H-ras codon 61 CTA mutations were detected in (4/8, 50%) ADBAQ-induced forestomach squamous cell papillomas and (10/24, 42%) squamous cell carcinomas, but not in the spontaneous forestomach tumors examined. H-ras codon 61 CGA mutation (6/24, 25%) was also detected in ADBAQ-induced forestomach squamous cell carcinomas. K-ras codon 61 A to T transversions and A to G transitions were prominent in ADBAQ-induced lung alveolar/bronchiolar adenomas and alveolar/bronchiolar carcinomas. The major finding of A to T transversions or A to G transitions in forestomach and lung tumors suggests that ADBAQ or its metabolites target adenine bases in the ras proto-oncogenes and that these mutations play a dominant role in multi-organ
AuthorsS Hayashi, H H Hong, K Toyoda, T V Ton, T R Devereux, R R Maronpot, J Huff, R C Sills
JournalToxicologic pathology (Toxicol Pathol) 2001 Jul-Aug Vol. 29 Issue 4 Pg. 422-9 ISSN: 0192-6233 [Print] United States
PMID11560247 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Anthraquinones
  • Carcinogens
  • Codon
  • 1-amino-2,4-dibromoanthraquinone
Topics
  • Adenocarcinoma, Bronchiolo-Alveolar (chemically induced, genetics, pathology)
  • Adenoma (chemically induced, genetics, pathology)
  • Administration, Oral
  • Animals
  • Anthraquinones (administration & dosage, toxicity)
  • Carcinogens (toxicity)
  • Carcinoma (chemically induced, genetics, pathology)
  • Carcinoma, Squamous Cell (chemically induced, genetics, pathology)
  • Codon
  • Exons
  • Female
  • Gene Frequency
  • Genes, ras (drug effects)
  • Lung Neoplasms (chemically induced, genetics, pathology)
  • Male
  • Mice
  • Mice, Inbred Strains
  • Papilloma (chemically induced, genetics)
  • Point Mutation
  • Polymorphism, Restriction Fragment Length
  • Polymorphism, Single-Stranded Conformational
  • Stomach Neoplasms (chemically induced, genetics, pathology)
  • Time Factors

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