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Introduction
Following Dr. Alton Ochsner's landmark observation, first reported in 1939 (1), of a relationship between smoking and lung cancer, a number of investigations have helped to establish, through retrospective and prospective studies, a definitive causal relationship (2-6).
More recently, the molecular and cellular foundations for this correlation have, to some extent, been clarified. Lung cancer is often a multistep, multifactorial disease involving both genetic and environmental components. Clearly, smoking is a major contributing factor; one in ten lifetime smokers develop lung cancer and more than 90% of lung cancers are correlated with smoking (7). Cigarette smoke mediates its carcinogenic effect, at least in part, through specific identified molecules that bind to and mutagenize DNA. Lesions that inactivate or downregulate tumor suppressor genes (the products of which, by definition, suppress tumorigenesis) and lesions that upregulate or inappropriately activate oncogenes (the products of which contribute to tumorigenesis) encourage the development of lung cancer. In addition, individuals may be inherently predisposed or resistant to lung cancer by genetic polymorphisms that influence activation of precarcinogens, catabolism of carcinogens, or DNA repair. As a more complete comprehension of the process unfolds, gene and drug therapies should provide early interventions that prevent dissemination of neoplastic cells and reduce fatalities associated with this devastating disease.
Developments
Identification of smoke-related pollutants
Lung cancer is the number one cause of cancer-related death in the U.S. and second only to cardiovascular disease overall. Because lung cancers are extremely angioinvasive and often metastasize from tumors that are too small to be readily detected, the 5-year survival rate after diagnosis is only 12% (8). Early cancer detection is clearly integral to effective treatment.
Approximately 3,800 specific carcinogenic agents (9) have been identified in cigarette smoke including polycyclic aromatic hydrocarbons such as benzopyrene (B(a)P), the activated form of which intercalates and damages DNA (10, 11) (see Figure 1). The active, or carcinogenic, form of BP is (+)-anti-7$bT, 8$aL-dihydroxy-9$aL, 10$aL-epoxy-7, 8, 9, 10-tetrahydrobenzo[a]pyrene or BPDE. BPDE binds to the N2 position of guanine and causes predominantly G:C to T:A transversions and very specific chromatin “hotspots” for DNA mutations (see p134 Abbreviations, Definitions, and Notes section for explanations of these and other genetic terms). The transversion may occur by either mispairing of the adducted guanine with adenine or...