COMPARISON OF PULMONARY O-6-METHYLGUANINE DNA ADDUCT LEVELS AND KI-RAS ACTIVATION IN LUNG-TUMORS FROM RESISTANT AND SUSCEPTIBLE MOUSE STRAINS

The role of O6-methylguanine (O6MG) DNA adduct formation and persisten ce in the formation of nitrosamino)-1-(3-pyridyl)-1-butanone(NNK)-indu ced lung tumors from resistant C57BL/6 and susceptible A/J mice was in vestigated. 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 carcin ogenesis in these resistant mice was examined. One day after treatment with 100 mg/kg NNK, O6MG adduct concentrations were twofold to eightf old higher in Clara cells and type II cells than in small cells or who le lungs from both mouse strains. The concentrations of O6MG in isolat ed 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 C5 7BL/6 mice was 4%. Only one of 22 lung tumors from C57BL/6 mice treate d with NNK contained an activated Ki-ras gene that was associated with an O6MG DNA adduct, whereas previous studies detected activated Ki-ra s oncogenes in most of the NNK-induced lung tumors analyzed from susce ptible A/J and resistant C3H mice. The small differences in formation and persistence of the O6MG adduct in whole lung or isolated lung cell s from A/J and C57BL/6 strains do not account for the differences in e ither susceptibility for tumor formation or activation of the Ki-ras g ene between these strains. In contrast to the low number of NNK-induce d tumors with Ki-ras mutations in the resistant mice, 11 of 20 lung tu mors from VC-treated mice contained activated Ki-ras genes. Neither p5 3 tumor suppressor gene mutations nor overexpression of the p53 protei n were detected in spontaneous or chemically induced lung tumors in C5 7BL/6 mice. Thus, although Ki-ras activation was detected in some tumo rs, pathways independent of ras activation and p53 inactivation also a ppear to be involved in lung tumorigenesis in this resistant mouse str ain. (C) 1993 Wiley-Liss, Inc.