Our overall goal is to develop biomarkers for chemoprevention studies of cigarette smoke-related cancers that can be translated to clinical studies in former smokers. To obtain this aim, we propose:
Specific Aim 1 : Develop biomarkers for chemoprevention of lung cancer in former smokers using a mouse model for lung cancer and related biological and molecular alterations;
and Specific Aim 2 : Develop biomarkers for chemoprevention of bladder cancer in ex-smokers using a rat model for urinary bladder cancer and associated biological and molecular alterations. Our hypothesis is that chemopreventive agents will decrease cancer incidence by modulating and reversing biological and molecular alterations in phenotypically normal tissue, precancerous tissues and tumors. Further, we hypothesize that the modulation of the biological and molecular alterations can be developed as biomarkers for chemoprevention in animal and clinical studies including studies in former smokers. To accomplish Aim 1, lung tumors will be induced in strain A mice by exposure to cigarette smoke, benzo(a)pyrene and 4-(Methyl nitrosamino)-1-(3- pyridyl)-1-butanone (NNK) and to accomplish Aim 2, bladder tumors will be induced in F344 rats by N-butyl-N-hydroxybutyl)nitrosamine (OH-BBN). After exposure to the carcinogens including cigarette smoke has ceased the animals will be administered the chemo-preventive agents: budesonide and the farnesyl transferase inhibitor, R115777 in the lung studies and budesonide, ketoprofen and sulindac in the bladder study. Biological and molecular alterations of cell proliferation, apoptosis, methylation of genes (both hypomethylation of protooncogenes and hypermethylation of tumor suppressor genes) and alteration in mRNA and protein expression will be determined in phenotypically normal tissues, precancerous lesions and tumors at different times during the progression to cancer. The ability of the chemopreventive agents to modulate and reverse these biological and molecular alterations in tissue and lesions will be determined in parallel with the ability of the agents to prevent cancer. Thus, biological and molecular alterations that are modulated in parallel with the prevention of cancer by the chemopreventive agents will be indicated as biomarkers for chemoprevention studies including those in former smokers where the agents will similarly be administered after exposure to cigarette smoke had ceased.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096129-04
Application #
6707998
Study Section
Special Emphasis Panel (ZCA1-SRRB-E (J2))
Program Officer
Steele, Vernon E
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$559,283
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Alyaqoub, Fadel S; Liu, Yue; Tao, Lianhui et al. (2008) Modulation by bexarotene of mRNA expression of genes in mouse lung tumors. Mol Carcinog 47:165-71
Alyaqoub, Fadel S; Tao, Lianhui; Kramer, Paula M et al. (2007) Prevention of mouse lung tumors and modulation of DNA methylation by combined treatment with budesonide and R115777 (Zarnestra MT). Carcinogenesis 28:124-9
Li, Long; Tao, Lianhui; Lubet, Ronald A et al. (2007) Modulation by budesonide of a CpG endonuclease in mouse lung tumors. Carcinogenesis 28:1499-503
Pereira, Michael A; Kramer, Paula M; Nines, Ronald et al. (2006) Prevention of mouse lung tumors by targretin. Int J Cancer 118:2359-62
Alyaqoub, Fadel S; Tao, Lianhui; Kramer, Paula M et al. (2006) Prevention of mouse lung tumors and modulation of DNA methylation by combined treatment with budesonide and R115777 (ZarnestraMT). Carcinogenesis 27:2442-7