Carcinogen biomarkers related to smoking and upper aerodigestive tract cancer

Abstract

Smoking is the major cause of upper aerodigestive tract cancers. Among the many constituents of tobacco smoke, polynuclear aromatic hydrocarbons and tobacco-specific nitrosamines are strongly implicated as causative factors for these cancers. The probability that these compounds will induce cancer in a given individual will depend on that person's ability to metabolically activate or detoxify them. Chronic production of DNA damage by these metabolically activated carcinogens is consistent with current concepts of carcinogenesis in which multiple genetic changes, such as activation of oncogenes or inactivation of tumor suppressor genes, appear to be critical. Chemopreventive agents which decrease the level of DNA damage should therefore decrease the risk for cancer. Biomarkers such as carcinogen-DNA adducts, carcinogen-hemoglobin adducts, and urinarymetabolites of carcinogens will indicate the amount of metabolically activated carcinogen which may damage DNA in an individual and can therefore be used as an index of risk. Selected biomarkers are discussed in this paper. These biomarkers of internal dose have great potential for application in chemoprevention trials.0 1993 Wiley-Liss, Inc.Key words: Carcinogen biomarkers, tobacco smoke carcinogens, polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines, hemoglobin adducts, DNAadducts, chemoprevention by isothiocyanates, phenethyl isothiocyanateSmoking has been established conclusively as an important cause of upper aerodigestive cancers including squamous cell, small cell, and adenocarcinoma of the lung, as well as oral, oropharyngeal, hypopharyngeal, laryngeal, and esophageal cancers [ 11. Shopland et al. [2] have estimated the risk of deaths from various cancers which are attributable to smoking. U.S. data for 1991 indicated that 90.3% of deaths from lung cancer, 91.5% from oral cancer, 81.2% from laryngeal cancer, and 78.2% from esophageal cancer in males were attributed to CAUSATIVE AGENTS FOR UPPER AERODIGESTIVE TRACT CANCERS IN TOBACCOPRODUCTSTobacco smoke contains approximately 4,000 identified compounds, of which at least 40 are known carcinogens in laboratory animals [ 1,4]. One can assess the possible contributions of these carcinogens t o upper aerodigestive cancers by considering their levels in tobacco smoke, their carcinogenic properties in laboratory animals, as well as biochemical evidence for their uptake and metabolic activation by smokers [ 1,461. Polycyclic aromatic hydrocarbons (PAHs) are well-characterized respiratory tract carcinogens. Benzo(a)pyrene [B(a)P, Fig. 11 is by far the most extensively studied of these compounds and has been regarded as a prototype for the PAH class. It is a potent respiratory carcinogen in rodents and occurs in mainstream cigarette smoke in amounts generally ranging from 2 0 4 0 ng per cigarette. The presence of B(a)P-DNA adducts in the lungs of smokers has been demonstrated and a correlation between induced levels of cytochrome P450lA1 in human lung and B(a)P-DNA adduct levels has been noted [7...

Trans -4-hydroxy-2-nonenal inhibits nucleotide excision repair in human cells: A possible mechanism for lipid peroxidation-induced carcinogenesis

“…These factors together may be an important reason why codon 249 of p53 gene is a mutational hotspot in hepatocellular carcinoma. Cigarette smoke is the major cause of lung cancer, and polycyclic aromatic hydrocarbons generated in cigarette smoke have been suggested as being responsible for the initiation and development of lung cancer (39). Previously, we have found that polycyclic aromatic hydrocarbons including BPDE preferentially bind at mutational hotspots in smoke-related lung cancer, such as codons 157, 158, 245, 248, 273, and 282, but not codon 249 (16,40).…”

Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair

“…Discussion CS is the major cause of lung cancer deaths, and 90% of all lung cancers in the United States are CS-related (28,29). CS contains Ͼ4,000 compounds, many of which, including PAHs, Nnitrosamines, aromatic amines, and metals, are not only mutagenic but also well established carcinogens in animal models (8,29,30). Therefore, it is reasonable to assume that these compounds contribute to CS-related lung carcinogenesis in humans.…”

Deposition of Cigarette Smoke Particles in the Human Respiratory Tract

“…Relating dosimetry to the mutational spectra of histologic typespeci c cancers may provide clues to why certain cancer types develop in particular anatomic locations while others do not (Weston and Bowman 1991). In addition, dosimetry could aid in the development of chemopreventive agents which target speci c lung cells and inhibit the progression stages of carcinogenesis (Wattenberg 1992;Hecht et al 1993Hecht et al , 1994. Muller et al (1990) presented a model of CSP deposition in the human respiratory tract that approximated the hygroscopic nature of CSP as being similar to that of NaCl.…”