Devereux T R, Belinsky S A, Maronpot R R, White C M, Hegi M E, Patel A C, Foley J F, Greenwell A, Anderson M W
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Mol Carcinog. 1993;8(3):177-85. doi: 10.1002/mc.2940080308.
The role of O6-methylguanine (O6MG) 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, O6MG 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 O6MG 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 O6MG 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 O6MG 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.
研究了O6-甲基鸟嘌呤（O6MG）DNA加合物的形成及其持久性在抗性C57BL/6和易感A/J小鼠中由4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）诱导的肺肿瘤形成过程中的作用。此外，还确定了用NNK或氨基甲酸乙烯酯（VC）处理的C57BL/6小鼠的肺肿瘤形成频率和Ki-ras激活情况，并研究了p53基因在这些抗性小鼠肺致癌作用中的作用。在用100mg/kg NNK处理一天后，Clara细胞和II型细胞中的O6MG加合物浓度比两种小鼠品系的小细胞或全肺中的浓度高2至8倍。两种小鼠品系中分离细胞中O6MG的浓度以相似的速率下降。在单次给予100mg/kg剂量的NNK后，18%的C57BL/6小鼠在27月龄时检测到肺肿瘤，在单次给予60mg/kg剂量的VC后，46%的这些小鼠检测到肺肿瘤。相比之下，未处理的C57BL/6小鼠的肿瘤发生率为4%。在用NNK处理的C57BL/6小鼠的22个肺肿瘤中，只有1个含有与O6MG DNA加合物相关的激活的Ki-ras基因，而先前的研究在从易感A/J和抗性C3H小鼠分析的大多数NNK诱导的肺肿瘤中检测到激活的Ki-ras癌基因。A/J和C57BL/6品系的全肺或分离的肺细胞中O6MG加合物的形成和持久性的微小差异并不能解释这些品系在肿瘤形成易感性或Ki-ras基因激活方面的差异。与抗性小鼠中NNK诱导的具有Ki-ras突变的肿瘤数量较少相反，在用VC处理的小鼠的20个肺肿瘤中，有11个含有激活的Ki-ras基因。在C57BL/6小鼠的自发或化学诱导的肺肿瘤中未检测到p53肿瘤抑制基因突变或p53蛋白的过表达。因此，尽管在一些肿瘤中检测到了Ki-ras激活，但在这种抗性小鼠品系的肺肿瘤发生过程中，似乎也涉及到独立于ras激活和p53失活的途径。
