Genetic Polymorphism and Lung Cancer: Animal Models of Tobacco Carcinogenesis

Smoking is a major risk factor for lung cancer which is the leading cause of death from cancer in Kentucky and in the United States. In spite of extensive research, the underlying mechanisms of how smoking causes cancer are poorly understood and it has been difficult to identify chemopreventive agents that will protect against smoking-mediated cancer. One of the reasons for this is a lack of a suitable animal model in which lung cancer can be produced experimentally by inhalation exposure to cigarette smoke. We hypothesize that since smokers who develop cancers have been found to lack or possess defective forms of cancer genes, it will be necessary to employ test animals that possess similarly defective genes to induce cigarette smoke-induced tumors. In this application we propose to test genetically modified mice lacking specific detoxification enzyme genes for their susceptibility to cigarette smoke-induced tumorigenesis. The main aim is to establish a suitable animal model which can be utilized (1) to examine the mechanisms of tobacco carcinogenesis, and, (2) for identification of chemopreventive agents that will protect against tobacco smoke carcinogenesis. It is expected that these studies will not only provide a suitable animal model but will also help identify target genes of smoke carcinogens.j