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Comparison of pulmonary O 6 ‐methylguanine dna adduct levels and Ki‐ ras activation in lung tumors from resistant and susceptible mouse strains
Author(s) -
Devereux Theodora R.,
White Catherine M.,
Hegi Monika E.,
Patel Arti C.,
Anderson Marshall W.,
Maronpot Robert R.,
Foley Julie F.,
Greenwell Arnold,
Belinsky Steven A.
Publication year - 1993
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.2940080308
Subject(s) - carcinogenesis , biology , microbiology and biotechnology , ratón , adduct , lung , carcinogen , lung cancer , dna , gene , cancer research , chemistry , immunology , medicine , biochemistry , organic chemistry
Abstract The role of O 6 ‐methylguanine (O 6 MG) DNA adduct formation and persistence in the formation of 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK)—induced lung tumors from resistant C57BL/6 and susceptible A/J mice was investigated. In addition, the frequencies of pulmonary tumor formation and Ki‐ ras activation were defined in C57BL/6 mice treated with NNK or vinyl carbamate (VC), and the role of the p53 gene in pulmonary carcinogenesis in these resistant mice was examined. One day after treatment with 100 mg/kg NNK, O 6 MG adduct concentrations were twofold to eightfold higher in Clara cells and type II cells than in small cells or whole lungs from both mouse strains. The concentrations of O 6 MG in isolated cells decreased at a similar rate in the two strains of mice. Lung tumors were detected by 27 mo of age in 18% of the C57BL/6 mice after a single 100 mg/kg dose of NNK and in 46% of these mice after a single 60 mg/kg dose of VC. In contrast, the tumor incidence in untreated C57BL/6 mice was 4%. Only one of 22 lung tumors from C57BL/6 mice treated with NNK contained an activated Ki‐ ras gene that was associated with an O 6 MG DNA adduct, whereas previous studies detected activated Ki‐ ras oncogenes in most of the NNK‐induced lung tumors analyzed from susceptible A/J and resistant C3H mice. The small differences in formation and persistence of the O 6 MG adduct in whole lung or isolated lung cells from A/J and C57BL/6 strains do not account for the differences in either susceptibility for tumor formation or activation of the Ki‐ ras gene between these strains. In contrast to the low number of NNK‐induced tumors with Ki‐ ras mutations in the resistant mice, 11 of 20 lung tumors from VC‐treated mice contained activated Ki‐ ras genes. Neither p53 tumor suppressor gene mutations nor overexpression of the p53 protein were detected in spontaneous or chemically induced lung tumors in C57BL/6 mice. Thus, although Ki‐ ras activation was detected in some tumors, pathways independent of ras activation and p53 inactivation also appear to be involved in lung tumorigenesis in this resistant mouse strain.