Tobacco smoke: chemical carcinogenesis and genetic lesions

Lung cancer is the primary cause of cancer-related death in the United States and smoking is the major contributing factor. An amazing array of carcinogenic and precarcinogenic agents has been identified in cigarette smoke. This review addresses the mechanisms by which some of the predominant lung carcinogens mutagenize DNA and explores some of the pivotal genes that are both susceptible to mutagenesis and contribute to the process of tumorigenesis and carcinogenesis. In addition, genes, gene products, and genetic polymorphisms, which curtail the processes leading to carcinogenesis, are discussed. The availability of clinically serviceable methods for analysis of genetic changes that can contribute to lung cancer is imperative to the development of timely, accurate, and cost-effective diagnostic and prognostic tests.A more thorough understanding of the step-wise conversion of precarcinogens to carcinogens, binding of carcinogens to DNA, mutation of DNA, DNA repair, and cellular destruction of carcinogens should contribute to the design of drugs that can modify these processes. In addition, introduction of genes (such as the p53 tumor supressor gene) into susceptible lung cells may impede carcinogenesis. Early stage clinical trials for the treatment of lung cancer using this and other genes are presently underway.