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[Cancer Research 61, 2472-2479, March 15, 2001]
© 2001 American Association for Cancer Research

Carcinogenesis

Modulation of Biomarkers by Chemopreventive Agents in Smoke-exposed Rats1

Alberto Izzotti, Roumen M. Balansky2, Francesco D’Agostini, Carlo Bennicelli, Steven R. Myers, Clinton J. Grubbs, Ronald A. Lubet, Gary J. Kelloff and Silvio De Flora3

Department of Health Sciences, University of Genoa, I-16132 Genoa, Italy [A. I., R. M. B., F. D’A., C. B., S. D. F.]; Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40292 [S. R. M.]; Chemoprevention Center, University of Alabama, Birmingham, Alabama 35294-3361 [C. J. B.]; and National Cancer Institute, Rockville, Maryland 20892 [R. A. L., G. J. K.]

Chemoprevention opens new perspectives in the prevention of cancer and other chronic degenerative diseases associated with tobacco smoking, exploitable in current smokers and, even more, in exsmokers and passive smokers. Evaluation of biomarkers in animal models is an essential step for the preclinical assessment of efficacy and safety of potential chemopreventive agents. Groups of Sprague Dawley rats were exposed whole body to a mixture of mainstream and sidestream cigarette smoke for 28 consecutive days. Five chemopreventive agents were given either with drinking water (N-acetyl-L-cysteine, 1 g/kg body weight/day) or with the diet (1,2-dithiole-3-thione, 400 mg; Oltipraz, 400 mg; phenethyl isothiocyanate, 500 mg; and 5,6-benzoflavone, 500 mg/kg diet). The monitored biomarkers included: DNA adducts in bronchoalveolar lavage cells, tracheal epithelium, lung and heart; oxidative damage to pulmonary DNA; hemoglobin adducts of 4-aminobiphenyl and benzo(a)pyrene-7,8-diol-9,10-epoxide; micronucleated and polynucleated alveolar macrophages and micronucleated polychromatic erythrocytes in bone marrow. Exposure of rats to smoke resulted in dramatic alterations of all investigated parameters. N-Acetyl-L-cysteine, phenylethyl isothiocyanate, and 5,6-benzoflavone exerted a significant protective effect on all alterations. 1,2-Dithiole-3-thione was a less effective inhibitor and exhibited both a systemic toxicity and genotoxicity in alveolar macrophages, whereas its substituted analogue Oltipraz showed limited protective effects in this model. Interestingly, combination of N-acetyl-L-cysteine with Oltipraz was the most potent treatment, resulting in an additive or more than additive inhibition of smoke-related DNA adducts in the lung and hemoglobin adducts. These results provide evidence for the differential ability of test agents to modulate smoke-related biomarkers in the respiratory tract and other body compartments and highlight the potential advantages in combining chemopreventive agents working with distinctive mechanisms.




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