Cigarette Smoke And Cancer

Cigarette smoke(CS) is a major cause of cancers of the lung, larynx, oral cavity and pharynx, esophagus, pancreas, kidney, and bladder (16). Worldwide, one in seven or 15% (1.1 million new cases per year) of all cancer cases are attributable to CS, 25% in men and 4% in women. Recent estimates indicate that CS causes approximately 80-90% of lung cancer in the United States (17). Smoking during pregnancy and passive exposure to CS may increase the risk of cancer for children and adults (18-20). These estimates do not include the disease resulting from smokeless tobacco (taken orally or as snuff), which is a substantial cause of cancer mortality, particularly on the Indian subcontinent (21).

Tobacco smoke is a complex mixture containing at least 40 different carcinogens, which mediate tumor initiation and promotion. These carcinogens include nitrosamine, polycyclic aromatic hydrocarbons (PAH), aromatic amines, unsaturated aldehydes (e.g., crotonaldehyde), and some phenolic compounds (acrolein). The most potent carcinogenic agent contained in CS is the nitrosamine 4-(methylnitrosoamino) -l-(3-pyridyl) -l-butanone (NNK); formed by nitrosation of nicotine, it is thought to be an important etiological factor in tobacco-smoke related human cancers (22). The NNK is a site-specific carcinogen in that, irrespective of the route of administration, NNK has remarkable specificity for the lung (23). Because side-stream smoke often contains higher amounts of NNKthan mainstream smoke, passive exposure to CS has been suggested to be quite harmful (22). An enzyme 11 beta-hydroxysteroid dehydrogenase 1(11 beta-HSD1), which is involved in metabolism of endogenous steroids, is also responsible for the metabolism of NNK. Thus inhibition of 11 beta-HSD1 can increase the circulating levels of NNK by impairing its metabolism. Ethanol has been shown to be a potent inhibitor of 11 beta-HSD (24) and thus may increase the risk of lung cancer for active or passive smokers. An alcohol consumption and cigarette smoking have also been shown to increases the frequency of p53, a tumor suppressor gene, mutation in lung cancer (25).

Cigarette smoke has been shown to induce aryl hydrocarbon hydroxylase (AHH) activity, an activator of respiratory tract carcinogens of the PAH (e.g., benzo[a] pyrene) group (26), in human pulmonary macrophages (27) and in patients with smoking-associated malignant cancers (28). It has been postulated that individuals with high activity of oxidative enzymes (cytochrome P-450 enzymes) or a low activity of detoxifying enzymes (e.g., glutathione s-transferase and epox-ide hydroxylase) may be at increased risk for cancer caused by CS (29). Low intake of dietary constituents with antioxidant properties such as P carotene, vitamin C, and vitamin E further increases the cancer risk in smokers (30).

Lung tumors from nonsmokers exhibit elevated NAD(P) H:(quinone-acceptor) oxidoreductase (QAO) activity compared to normal tissue, but tumors from smokers show increases in tumor QAO (31). This could influence the response of these tumors to quinone drugs (commonly used to treat cancer) or toxic agents that are metabolized by QAO. Quinone anticancer drugs are activated to alkylating species by reduction to hydroquinone. Metabolism by QAO is responsible for the formation of alkylating species from doxorubicin (32) and other cytotoxic drugs (33).

Another possible mechanism by which CS can cause cancer involves the effects of PAH on the p53 gene. For instance, exposure of cells to benzo(a)pyrene adducts can induce the same mutation in p53 as is found in 60% of all lung cancers (34). Also exposure of cells to PAH and its metabolites results in a rapid accumulation of the p53 gene product (35,36) through activation of a transcription factor, NF-kB (37).

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