? p53 mutations are found in more than 50% of all human cancers, including lung cancer. These mutations strongly select for p53 proteins that fail to bind to DNA in a sequence-specific fashion. The p53 protein is a tetramer and requires zinc ions for its activity as DNA-binding transcription Lung cancer is the leading cause of cancer death in the United States and the poor lung cancer survival rates argue strongly for new approaches to control this devastating disease. Chemoprevention represents an approach to reverse, suppress, or prevent lung carcinogenesis. Over 80% of lung cancers are attributed to tobacco and carcinogens from cigarette smoke. Even after quitting smoking, former smokers remain at high risk and account for over 50% of current lung cancer cases. With the recent developments in microarray technology, increased insights in lung carcinogenesis will led to the development of targeted intervention and optimism for new chemopreventive approaches to prevent tobacco-related lung cancer, especially in former smokers. We have developed a transgenic mouse model for smoking-related lung cancer by exposure to tobacco carcinogen. The dominant-negative mutant p53 transgene is specifically expressed in the bronchial epithelium under the Clara Cell Specific Protein (CCSP) promoter which results in increased susceptibility to both spontaneous and BaP-induced lung cancer, hence offering a preclinical model for studying chemoprevention of tobacco-related lung cancer.
The specific aims are as follows: (1) To establish a mouse model to mimic high risk former smokers and to identify surrogate biomarkers for lung cancer; (2) To determine the efficacy of chemopreventive agents and to validate the use of surrogate biomarkers as endpoints for chemoprevention; (3) To evaluate the use of magnetic resonance imaging (MRI) for assessing tumor growth and and efficacy of chemopreventive agents. ? ? ?
| Koshiji, Minori; Kumamoto, Kensuke; Morimura, Keiichirou et al. (2007) Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity. World J Gastroenterol 13:2803-10 |
| Pratt, Timothy S; Pincus, Seth H; Hale, Martha L et al. (2007) Oropharyngeal aspiration of ricin as a lung challenge model for evaluation of the therapeutic index of antibodies against ricin A-chain for post-exposure treatment. Exp Lung Res 33:459-81 |
| Zhang, Ping; Tchou-Wong, Kam-Meng; Costa, Max (2007) Egr-1 mediates hypoxia-inducible transcription of the NDRG1 gene through an overlapping Egr-1/Sp1 binding site in the promoter. Cancer Res 67:9125-33 |
