Research Article

Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from Swiss (CD-1) male mice exposed transplacentally to AZT†‡

  1. Hue-Hua L. Hong1,*,
  2. June Dunnick2,
  3. Ronald Herbert1,
  4. Theodora R. Devereux1,
  5. Yongbaek Kim1,
  6. Robert C. Sills1

Article first published online: 4 JAN 2006

DOI: 10.1002/em.20197

Issue

Environmental and Molecular Mutagenesis

Environmental and Molecular Mutagenesis

Volume 48, Issue 3-4, pages 299–306, April - May 2007

Additional Information

How to Cite

Hong, H.-H. L., Dunnick, J., Herbert, R., Devereux, T. R., Kim, Y. and Sills, R. C. (2007), Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from Swiss (CD-1) male mice exposed transplacentally to AZT. Environ. Mol. Mutagen., 48: 299–306. doi: 10.1002/em.20197

Author Information

  1. 1

    Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina

  2. 2

    Toxicology Operations Branch, National Institute of Environmental HealthSciences, Research Triangle Park, North Carolina

*Molecular Pathology Group, Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, MD E1-07, 111 Alexander Drive, Research Triangle Park, NC 27709, USA

  1. †

    This article is a US Government work and, as such, is in the public domain in the United States of America.

  2. ‡

    Invited article on the genotoxicity of perinatal NRTI therapy.

Publication History

  1. Issue published online: 19 MAR 2007
  2. Article first published online: 4 JAN 2006

Funded by

  • National Institute of Health
  • National Institute of Environmental Health Sciences

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Keywords:

  • 3′-azido-3′-deoxythymidine;
  • AZT;
  • transplacental carcinogenesis;
  • lung cancer;
  • Swiss mice;
  • K-ras oncogene;
  • p53 tumor suppressor gene

Abstract

A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD-1) mice to 0, 50, 100, 200, or 300 mg of 3′-azido-3′-deoxythymidine (AZT)/kg bw/day, through a 18 to 19-day gestation [National Toxicology Program, NIH Pub. No. 04-4458, 2004]. The incidences of alveolar/bronchiolar adenomas and carcinomas, in the 200 and 300 mg/kg male treatment groups, were significantly greater than that of the controls. In the present study, we evaluated the benign and malignant lung neoplasms from this bioassay for point mutations, in the K-ras and p53 cancer genes that are often mutated in human lung tumors. K-ras and p53 mutations were detected by cycle sequencing of polymerase chain reaction-amplified DNA, isolated from formalin-fixed, paraffin-embedded neoplasms. K-ras mutations were detected in 25 of 38 (66%) of the AZT-induced lung tumors, and the predominant mutations were codon 12 G→T transversions. p53 mutations were detected in 32 of 38 (84%) of the AZT-induced lung tumors, with the predominant mutations being exon 8, codon 285 A→T transversions, and exon 6, codon 198 T→A transversions. No K-ras or p53 mutations were detected in five tumors, examined from control mice. The patterns of mutations identified in the lung tumors suggest that incorporation of AZT or its metabolites into DNA, oxidative stress, and genomic instability may be the contributing factors to the mutation profile and development of lung cancer in these mice. Environ. Mol. Mutagen., 2006. Published 2006 Wiley-Liss, Inc.

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