| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Laboratory of Molecular Toxicology [S. A. B., T. R. D., M. W. A.] and Chemical Pathology Branch [R. R. M.], National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 and Department of Pathology, Medical College of Ohio, Toledo, Ohio 43614 [G. D. S.]
Lung and liver tumors were induced in female A/J mice after treatment for 7 weeks (3 times/week, i.p.) with either 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (50 mg/kg) or nitrosodimethylamine (NDMA) (3 mg/kg). Both compounds can be activated via 
-hydroxylation to methylating agents, while NNK may also undergo hydroxylation at the N-methyl carbon to form a pyridyloxobutylated adduct. The purpose of these studies was to identify and characterize the activated oncogenes present in tumors induced by NDMA and NNK. Following transfection of high molecular weight DNA onto NIH/3T3 mouse fibroblasts, transforming genes were detected in 90% of both NNK- (10 of 11) and NDMA- (9 of 10) induced lung tumors. In contrast, transformation of NIH/3T3 fibroblasts was observed only in 40% (2 of 5) and 13% (1 of 8) of the liver tumors from NNK- and NDMA-treated mice, respectively. Southern blot analysis indicated that the transforming gene present in all lung tumors was an activated K-ras oncogene. Both rear-ranged bands and amplified signals were detected in the transfectants. The one transformant from the NDMA-induced liver tumor contained an activated K-ras gene. In contrast, the two liver transformants from NNK-induced tumors did not contain an activated ras or raf gene. Hybridization with oligonucleotide probes that were centered around either codon 12 or 61 of the K-ras gene were utilized to localize the mutations. Activation of this gene appeared to occur largely via a mutation in codon 12 (15 of 20 transformants) and was observed with a similar frequency in pulmonary tumors induced by either compound. The remaining mutations were found in codon 61. The specific mutation within these two codons was determined by amplifying the exon containing the base change, followed by direct sequencing. With one exception the mutation observed in codon 12 was a GC to AT transition (GGT to GAT). One transformant contained a GC to TA transversion. The activating mutation detected in codon 61 was always an AT to GC transition of the middle A (CAA to CGA). The GC to AT mutation observed in codon 12 is consistent with the formation of the O6-methylguanine adduct. Similar concentrations (23 to 32 pmol/µmol deoxyguanosine) of this promutagenic adduct were detected in lungs during treatment with either NNK or NDMA. A comparison of the mutation patterns observed previously in spontaneous lung tumors from A/J mice with those detected in NNK- and NDMA-induced tumors indicates that chemically mediated activation of the K-ras gene occurs via a direct genotoxic mechanism involving the formation of the O6-methylguanine adduct. Almost 100% of the mutations in codon 12 were GC to AT transitions in chemically induced tumors, while this base change was present in only 50% of the spontaneous tumors with codon 12 mutations. The fact that the mutation profiles observed for activation of the K-ras gene by NNK and NDMA were identical indicates that DNA methylation and not pyridyloxobutylation is most likely the major pathway involved in the induction of pulmonary neoplasia by NNK.
1 To whom requests for reprints should be addressed.
Received 3/27/89. Revised 6/26/89. Accepted 7/ 6/89.
This article has been cited by other articles:
|
|
 |
|
  M. Majidi, H. A. Al-Wadei, T. Takahashi, and H. M. Schuller Nongenomic {beta} Estrogen Receptors Enhance {beta}1 Adrenergic Signaling Induced by the Nicotine-Derived Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Human Small Airway Epithelial Cells Cancer Res., July 15, 2007; 67(14): 6863 - 6871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. McClelland, S. L. Carskadon, L. Zhao, E. S. White, D. G. Beer, M. B. Orringer, A. Pickens, A. C. Chang, and D. A. Arenberg Diversity of the Angiogenic Phenotype in Non-Small Cell Lung Cancer Am. J. Respir. Cell Mol. Biol., March 1, 2007; 36(3): 343 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. P. Stabile, J. S. Lyker, S. R. Land, S. Dacic, B. A. Zamboni, and J. M. Siegfried Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer Carcinogenesis, August 1, 2006; 27(8): 1547 - 1555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Hutt, B. R. Vuillemenot, E. B. Barr, M. J. Grimes, F. F. Hahn, C. H. Hobbs, T. H. March, A. P. Gigliotti, S. K. Seilkop, G. L. Finch, et al. Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways Carcinogenesis, November 1, 2005; 26(11): 1999 - 2009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Belinsky Silencing of genes by promoter hypermethylation: key event in rodent and human lung cancer Carcinogenesis, September 1, 2005; 26(9): 1481 - 1487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Mauderly, A. P. Gigliotti, E. B. Barr, W. E. Bechtold, S. A. Belinsky, F. F. Hahn, C. A. Hobbs, T. H. March, S. K. Seilkop, and G. L. Finch Chronic Inhalation Exposure to Mainstream Cigarette Smoke Increases Lung and Nasal Tumor Incidence in Rats Toxicol. Sci., October 1, 2004; 81(2): 280 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yang, Z. Zhang, A. B. Mukherjee, and R. I. Linnoila Increased Susceptibility of Mice Lacking Clara Cell 10-kDa Protein to Lung Tumorigenesis by 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a Potent Carcinogen in Cigarette Smoke J. Biol. Chem., July 9, 2004; 279(28): 29336 - 29340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Pulling, B. R. Vuillemenot, J. A. Hutt, T. R. Devereux, and S. A. Belinsky Aberrant Promoter Hypermethylation of the Death-Associated Protein Kinase Gene Is Early and Frequent in Murine Lung Tumors Induced by Cigarette Smoke and Tobacco Carcinogens Cancer Res., June 1, 2004; 64(11): 3844 - 3848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R.K. Sticha, P. M.J. Kenney, G. Boysen, H. Liang, X. Su, M. Wang, P. Upadhyaya, and S. S. Hecht Effects of benzyl isothiocyanate and phenethyl isothiocyanate on DNA adduct formation by a mixture of benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mouse lung Carcinogenesis, September 1, 2002; 23(9): 1433 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, D. L. Weddle, P. E. Thomas, B. Zheng, A. Castonguay, H. M. Schuller, and M. S. Miller Low Levels of Expression of Cytochromes P-450 in Normal and Cancerous Fetal Pancreatic Tissues of Hamsters Treated with NNK and/or Ethanol Toxicol. Sci., August 1, 2000; 56(2): 313 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. P. Encell and L. A. Loeb Enhanced in vivo repair of O4-methylthymine by a mutant human DNA alkyltransferase Carcinogenesis, July 1, 2000; 21(7): 1397 - 1402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Lantry, Z. Zhang, R. Yao, K. A. Crist, Y. Wang, J. Ohkanda, A. D. Hamilton, S. M. Sebti, R. A. Lubet, and M. You Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone Carcinogenesis, January 1, 2000; 21(1): 113 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Qin, H. Zhou, L. Liu, and S. L. Gerson Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis Carcinogenesis, September 1, 1999; 20(9): 1667 - 1673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. C. Wei, R. L. Chang, K. A. Merkler, M. Gwynne, X. X. Cui, B. Murthy, M.-T. Huang, J.-G. Xie, Y.-P. Lu, Y.-R. Lou, et al. Dose-dependent mutation profile in the c-Ha-ras proto-oncogene of skin tumors in mice initiated with benzo[a]pyrene Carcinogenesis, September 1, 1999; 20(9): 1689 - 1696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Eileen Dolan, B. L. McRae, E. Ferries-Rowe, M. Belanich, G. A. van Seventer, J. Guitart, D. Pezen, T. M. Kuzel, and D. B. Yarosh O6-Alkylguanine-DNA Alkyltransferase in Cutaneous T-Cell Lymphoma: Implications for Treatment with Alkylating Agents Clin. Cancer Res., August 1, 1999; 5(8): 2059 - 2064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Esteller, S. R. Hamilton, P. C. Burger, S. B. Baylin, and J. G. Herman Inactivation of the DNA Repair Gene O6-Methylguanine-DNA Methyltransferase by Promoter Hypermethylation is a Common Event in Primary Human Neoplasia Cancer Res., February 1, 1999; 59(4): 793 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Liu, X. Qin, and S. L. Gerson Reduced lung tumorigenesis in human methylguanine DNA—methyltransferase transgenic mice achieved by expression of transgene within the target cell Carcinogenesis, February 1, 1999; 20(2): 279 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Winn, P. M. Kim, and P. G. Wells Investigation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone for In Vivo and In Vitro Murine Embryopathy and Embryonic ras Mutations J. Pharmacol. Exp. Ther., December 1, 1998; 287(3): 1128 - 1135. [Abstract] [Full Text]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
