At UCHSC, we have assembled mature Genomics and Proteomics and mouse carcinogenesis groups to study preclinical chemoprevention of lung cancer in former-smokers. Our rationale is that anti-inflammatory drugs inhibit chemically-induced lung tumorigenesis, early lung lesions are reversible, and no verified biomarkers exist for human lung neoplasia. Mouse hyperplastic foci and microadenomas model the small nodules present in the lungs of former smokers, and a better understanding of the progression to cancer will lend insight into human lung cancer chemoprevention. A two-stage carcinogenesis regimen, in which 3-methylcholanthrene (MCA) is injected ip followed by four weekly ip doses of butylated hydroxytolulene (BHT), induces these lung lesions in male BALB mice. Budesonide, a synthetic glucocorticoid, and three other anti-inflammatory drugs, each with a unique mechanism of action, will be administered (orally) singly and in combination after foci and microadenomas have developed. The three other drugs are LM4111 (a COX-2 specific inhibitor), PBIT (an iNOS-specific inhibitor), and Iloprost (a stable prostacyclin agonist). The number of foci, and the number and sizes of microadenomas and pleural surface adenomas will be quantified at established time points up to 20 weeks after the MCA injection. Several proteins whose expression increases in early mouse lung lesions will be examined by immunohistochemistry to see if they can predict successful chemoprevention. These include pro-inflammatory enzymes (COX-1, COX-2, and iNOS) and hnRNP proteins (AUF1 , HuR, and A1). We have combined two global strategies, genomics and proteomics, as discovery tools for novel surrogate markers. RNA and protein expression patterns will be examined by microarray, LC/MS/MS, and 2D-PAGE/MS analyses, respectively. Expression in normal lungs will be compared with dissectable adenomas, and then our analyses will move proximally to examine samples more practically obtainable from humans (bronchoalveolar lavage cells and fluid, and serum). Our goals are: (1) to successfully inhibit lung tumor progression when anti- inflammatory drugs are applied after early lesions have forms; and (2) to identify novel early-stage predictive biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096133-02
Application #
6604209
Study Section
Special Emphasis Panel (ZCA1-SRRB-E (J2))
Program Officer
Steele, Vernon E
Project Start
2002-06-28
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$520,008
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Zerbe, Laura K; Dwyer-Nield, Lori D; Fritz, Jason M et al. (2008) Inhibition by erlotinib of primary lung adenocarcinoma at an early stage in male mice. Cancer Chemother Pharmacol 62:605-20
Stearman, Robert S; Dwyer-Nield, Lori; Grady, Michael C et al. (2008) A macrophage gene expression signature defines a field effect in the lung tumor microenvironment. Cancer Res 68:34-43
Peebles, Katherine A; Dwyer-Nield, Lori D; Malkinson, Alvin M (2007) Altered expression of splicing factor, heterogeneous nuclear ribonucleoprotein A2/B1, in mouse lung neoplasia. Mol Carcinog 46:887-900
Stearman, Robert S; Grady, Michael C; Nana-Sinkam, Patrick et al. (2007) Genetic and epigenetic regulation of the human prostacyclin synthase promoter in lung cancer cell lines. Mol Cancer Res 5:295-308
Redente, Elizabeth F; Orlicky, David J; Bouchard, Ronald J et al. (2007) Tumor signaling to the bone marrow changes the phenotype of monocytes and pulmonary macrophages during urethane-induced primary lung tumorigenesis in A/J mice. Am J Pathol 170:693-708
O'Donnell, E Paul; Zerbe, Laura K; Dwyer-Nield, Lori D et al. (2006) Quantitative analysis of early chemically-induced pulmonary lesions in mice of varying susceptibilities to lung tumorigenesis. Cancer Lett 241:197-202
Dwyer-Nield, Lori D; Srebernak, Mary C; Barrett, Bradley S et al. (2005) Cytokines differentially regulate the synthesis of prostanoid and nitric oxide mediators in tumorigenic versus non-tumorigenic mouse lung epithelial cell lines. Carcinogenesis 26:1196-206
Bauer, Alison K; Dixon, Darlene; DeGraff, Laura M et al. (2005) Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. J Natl Cancer Inst 97:1778-81
Stearman, Robert S; Dwyer-Nield, Lori; Zerbe, Laura et al. (2005) Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol 167:1763-75
Malkinson, Alvin M (2005) Role of inflammation in mouse lung tumorigenesis: a review. Exp Lung Res 31:57-82

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