Cigarette smoking causes 30% of all cancer mortality in the developed world. Tobacco-specific nitrosamines, the subject of this proposal, are accepted causes of cancer in people who use tobacco products. The two most carcinogenic of these compounds- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN)- are known human carcinogens according to IARC. Our laboratory is the acknowledged world leader in studies on mechanisms of tobacco-specific nitrosamine carcinogenicity, research that has been continually funded by NCI grants since 1976, including the current MERIT award. Our overall goal is to understand mechanisms by which tobacco products cause cancer and use this information to develop new approaches to tobacco control and prevention of tobacco-induced cancer. The current project period of this grant, which began in 2004, has been exceptionally productive. Twenty-one original peer-reviewed manuscripts and 12 reviews/book chapters have been published or submitted as of June, 2007. A full one page abstract and progress report are found on pages 19-29 of this application. We propose to continue this research with the following broad objectives: 1. Extend our new MS methods for DMA adduct analysis to include the pyridylhydroxybutyl and methyl adducts of NNAL and the 5'- hydroxylation adducts of NNN and improve the sensitivity of these methods. 2. Improve sensitivity and high throughput for measurement of the NNK metabolite NNAL in human blood and urine, and apply these methods in nested case control studies in which pre-diagnosis samples have been stored from smokers who developed lung cancer and from matched controls. 3. Identify the receptor(s) in the rat lung that specifically binds the NNK metabolite (S)-NNAL 4. Further develop the toenail biomarkers for NNAL and cotinine. 5. Determine the structure of an inhibitor of carcinogen metabolic activation, which we have identified in human lung microsomes. 6. Continue our research on inter-individual differences in human metabolic activation and detoxification of tobacco-specific nitrosamines, and on the endogenous formation of these carcinogens in humans. The results of these studies should provide important new data which will be critical for developing new approaches to the prevention of tobacco-induced cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA081301-14
Application #
8225302
Study Section
Special Emphasis Panel (NSS)
Program Officer
Johnson, Ronald L
Project Start
1999-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
14
Fiscal Year
2012
Total Cost
$500,375
Indirect Cost
$169,001
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Khammanivong, Ali; Anandharaj, Arunkumar; Qian, Xuemin et al. (2016) Transcriptome profiling in oral cavity and esophagus tissues from (S)-N'-nitrosonornicotine-treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis. Mol Carcinog 55:2168-2182
Hecht, Stephen S; Stepanov, Irina; Carmella, Steven G (2016) Exposure and Metabolic Activation Biomarkers of Carcinogenic Tobacco-Specific Nitrosamines. Acc Chem Res 49:106-14
Yershova, Katrina; Yuan, Jian-Min; Wang, Renwei et al. (2016) Tobacco-specific N-nitrosamines and polycyclic aromatic hydrocarbons in cigarettes smoked by the participants of the Shanghai Cohort Study. Int J Cancer 139:1261-9
Zabala, Valerie; Tong, Ming; Yu, Rosa et al. (2015) Potential contributions of the tobacco nicotine-derived nitrosamine ketone (NNK) in the pathogenesis of steatohepatitis in a chronic plus binge rat model of alcoholic liver disease. Alcohol Alcohol 50:118-31
Ma, Bin; Villalta, Peter W; Zarth, Adam T et al. (2015) Comprehensive High-Resolution Mass Spectrometric Analysis of DNA Phosphate Adducts Formed by the Tobacco-Specific Lung Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Res Toxicol 28:2151-9
Kotandeniya, Delshanee; Carmella, Steven G; Pillsbury, Makenzie E et al. (2015) Combined analysis of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in the urine of cigarette smokers and e-cigarette users. J Chromatogr B Analyt Technol Biomed Life Sci 1007:121-6
Kotandeniya, Delshanee; Carmella, Steven G; Ming, Xun et al. (2015) Combined analysis of the tobacco metabolites cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in human urine. Anal Chem 87:1514-7
Thomas, Janet L; Hecht, Stephen S; Luo, Xianghua et al. (2014) Thirdhand tobacco smoke: a tobacco-specific lung carcinogen on surfaces in smokers' homes. Nicotine Tob Res 16:26-32
Hecht, Stephen S; Szabo, Eva (2014) Fifty years of tobacco carcinogenesis research: from mechanisms to early detection and prevention of lung cancer. Cancer Prev Res (Phila) 7:1-8
Balbo, Silvia; Johnson, Charles S; Kovi, Ramesh C et al. (2014) Carcinogenicity and DNA adduct formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and enantiomers of its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in F-344 rats. Carcinogenesis 35:2798-806

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