Reference SummaryYou M, Carcinogenesis 1992 Sep;13(9):1583-6

Title

Mutagenesis of the K-ras protooncogene in mouse lung tumors induced by N-ethyl-N-nitrosourea or N-nitrosodiethylamine.

Authors

You M; Wang Y; Lineen AM; Gunning WT; Stoner GD; Anderson MW

Journal

Carcinogenesis

Volume

13

Issue

9

Year

1992

Pages

1583-6

Abstract

The role of ras gene activation in the development of lung tumors induced by N-ethyl-N-nitrosourea (ENU) and N-nitrosodiethylamine (DEN) was evaluated in the A/J mouse, a strain susceptible to chemically induced lung tumors. DNAs isolated from both ENU- and DEN-induced lung tumors were screened for activating mutations in the K-ras gene by utilizing the polymerase chain reaction (PCR) and direct sequence analysis. Mutations in the K-ras gene were detected in 11 of 11 ENU-induced tumors and 23 of 28 DEN-induced tumors. In ENU-induced tumors, there were three GC----AT transitions in the second base of codon 12, and seven AT----GC transitions and one AT----TA transversion in the second base of codon 61. A similar spectrum of K-ras mutations was observed in DEN-induced lung tumors: five GC----AT transitions and two GC----TA transversions in the second base of codon 12, and sixteen AT----GC transitions at the second base of codon 61. Ninety-one percent (31/34) of the observed mutations are consistent with the formation of the promutagenic O4-ethylthymine and O6-ethylguanine adducts in DNA. Therefore, lung tumors from the A/J mouse induced by DEN and ENU could be initiated by the interaction of reactive metabolites with specific sites in the K-ras gene. This is the first clear example of activation of the K-ras gene by ethylating agents in a rodent lung tumor system.

Links

J:70504 – MGI References
1394843 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
A/J Lung adenoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

A/J Lung adenoma
  • N-diethylnitrosamine (N,N-diethylnitrosamine) (N-nitrosodiethylamine) (NDEA) (diethylnitrosamine) (DEN)
Lung

observed

A/J Lung tumor Lung

observed