Point mutation of K-ras gene in cisplatin-induced lung tumours in A/J mice

Lung Cancer. 2007 Oct;58(1):15-20. doi: 10.1016/j.lungcan.2007.05.012. Epub 2007 Jul 2.

Abstract

The risks of secondary lung cancer in patients with early stage non-small and small cell lung cancers are estimated to be 1-2% and 2-10% per patient per year, respectively. Surprisingly, the incidence of second primary cancer in locally advanced non-small cell lung cancer at 10 years, following cisplatin-based chemotherapy with concurrent radiotherapy, increases to 61%. Those patients, on the road to being cured, cannot overlook the possibility of developing a second primary cancer. We developed a second primary lung cancer model using cisplatin as a carcinogen in A/J mice to screen for chemopreventive agents for a second malignancy. In the primary lung tumour model, 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo(a)pyrene (BaP), urethane induces specific K-ras mutations in codon 12, codon 12, and codon 61, respectively, in the A/J mice. In this study, we investigated the mechanisms of carcinogenicity by cisplatin in the A/J mice. In the cisplatin-induced tumours, we found no K-ras codon 12 mutation, which is the major mutation induced by NNK or BaP. K-ras gene mutations in codon 13 and codon 61 were found in one tumour (4%) and five tumours (17.8%), respectively. These findings suggest that cisplatin is partially related to K-ras codon 61 mutations, and that the mechanism of carcinogenicity by cisplatin is different from that by NNK or BaP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / chemically induced
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Adenocarcinoma / prevention & control
  • Animals
  • Benzo(a)pyrene / toxicity
  • Carcinogens / toxicity*
  • Carcinoma, Non-Small-Cell Lung / chemically induced
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / prevention & control
  • Cisplatin / adverse effects
  • Cisplatin / toxicity*
  • Codon
  • Female
  • Genes, ras*
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control
  • Mice
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / prevention & control
  • Neoplasms, Second Primary / chemically induced
  • Neoplasms, Second Primary / drug therapy
  • Neoplasms, Second Primary / genetics*
  • Neoplasms, Second Primary / prevention & control
  • Nitrosamines / toxicity
  • Point Mutation*

Substances

  • Carcinogens
  • Codon
  • Nitrosamines
  • Benzo(a)pyrene
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Cisplatin