Recent epidemiological studies continue to provide evidence that tobacco smoking is an independent risk factor for cervical cancer. Literature data also identifies human papillomaviruses (HPV) as an important etiological factor in the development of this disease. However, only a small population of HPV-infected individuals will develop cervical cancer. In addition, the transfection of human cervical cells with HPV immortalizes those cells but does not make them carcinogenic. It has, therefore, been suggested that other genetic changes are needed for the development of malignancy. These changes may result from oxidative damage or alkylation caused by tobacco derived carcinogens. We have demonstrated that these tobacco carcinogens are present in human cervical mucus and can be metabolically activated to genotoxic intermediates that can damage cervical DNA. It is our hypothesis that genetic damage induced by tobacco-derived carcinogens can lead to mutations of proto-oncogenes (e.g. c-myc, H- and K-ras, and c-erbB). Thus, genetic damaged induced by B[a]P and/or NNK combined with HPV-induced deactivation of tumor suppresser genes and inhibition of apoptosis can be expected to lead to the development of cervical cancer. Test our hypotheses we propose the following specific aims: (1) Develop an appropriate animal model to determine the role of carcinogenic activity of TSNA, PAH and HPV individually and in combination; and HPV transgenic mouse available in the laboratory of our collaborator is prerequisite to achieve the goals of this aim. (2) Examine the metabolism of NNK, NNAL and B[a]P in normal and HPV 16-immortalized human cervical cells and characterize enzymes responsible for their metabolic activation. (3) Evaluate the capacity of NNK, NNAL and B[a]P to induce malignant transformation to human cervical cells immortalized with HPV-16 as compared to controls. (4) Carry out a pilot study to establish the feasibility and conditions for a case-control study of the association between exposure to tobacco carcinogens (using representative biomarkers derived from the animal studies) and risk of cervical dysplasia/cancers, and risk modification by HPV infections. The studies proposed in this Project will provide important knowledge that is requisite to our understanding of the association of HPV infection and tobacco usage as it relates to the mechanism of induction of cervical neoplasias in humans. These studies will also provide a foundation to later test the chemopreventive efficacy of various chemopreventive agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA070972-05A2
Application #
6434442
Study Section
Project Start
1996-06-17
Project End
2006-02-28
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
5
Fiscal Year
2001
Total Cost
$295,892
Indirect Cost
Name
Institute for Cancer Prevention
Department
Type
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Chen, Kun-Ming; Guttenplan, Joseph B; Zhang, Shang-Min et al. (2013) Mechanisms of oral carcinogenesis induced by dibenzo[a,l]pyrene: an environmental pollutant and a tobacco smoke constituent. Int J Cancer 133:1300-9
Richie Jr, John P; Muscat, Joshua E; Ellison, Irina et al. (2011) Association of selenium status and blood glutathione concentrations in blacks and whites. Nutr Cancer 63:367-75
Waggoner, Steven E; Darcy, Kathleen M; Tian, Chunqiao et al. (2010) Smoking behavior in women with locally advanced cervical carcinoma: a Gynecologic Oncology Group study. Am J Obstet Gynecol 202:283.e1-7
Bortner Jr, James D; Das, Arunangshu; Umstead, Todd M et al. (2009) Down-regulation of 14-3-3 isoforms and annexin A5 proteins in lung adenocarcinoma induced by the tobacco-specific nitrosamine NNK in the A/J mouse revealed by proteomic analysis. J Proteome Res 8:4050-61
Das, Arunangshu; Bortner, James; Desai, Dhimant et al. (2009) The selenium analog of the chemopreventive compound S,S'-(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea is a remarkable inducer of apoptosis and inhibitor of cell growth in human non-small cell lung cancer. Chem Biol Interact 180:158-64
Prokopczyk, Bogdan; Sinha, Indu; Trushin, Neil et al. (2009) Gene expression profiles in HPV-immortalized human cervical cells treated with the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Biol Interact 177:173-80
Melikian, Assieh A; Chen, Kun-Ming; Li, Heyi et al. (2008) The role of nitric oxide on DNA damage induced by benzene metabolites. Oncol Rep 19:1331-7
Chang, Sung Il; El-Bayoumy, Karam; Sinha, Indu et al. (2007) 4-(Methylnitrosamino)-I-(3-pyridyl)-1-butanone enhances the expression of apolipoprotein A-I and Clara cell 17-kDa protein in the lung proteomes of rats fed a corn oil diet but not a fish oil diet. Cancer Epidemiol Biomarkers Prev 16:228-35
Chen, Kun-Ming; Spratt, Thomas E; Stanley, Bruce A et al. (2007) Inhibition of nuclear factor-kappaB DNA binding by organoselenocyanates through covalent modification of the p50 subunit. Cancer Res 67:10475-83
Melikian, Assieh A; Djordjevic, Mirjana V; Hosey, James et al. (2007) Gender differences relative to smoking behavior and emissions of toxins from mainstream cigarette smoke. Nicotine Tob Res 9:377-87

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