Modulation of biomarkers by chemopreventive agents in smoke-exposed rats

Chemoprevention opens new perspectives in the prevention of cancer and othe r chronic degenerative diseases associated with tobacco smoking, exploitabl e in current smokers and, even more, in exsmokers and passive smokers. Eval uation of biomarkers in animal models is an essential step for the preclini cal assessment of efficacy and safety of potential chemopreventive agents. Groups of Sprague Dawley rats were exposed whole body to a mixture of mains tream and sidestream cigarette smoke for 28 consecutive days. Five chemopre ventive 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; Ol tipraz, 400 mg; phenethyl isothiocyanate, 500 mg; and 5,6-benzoflavone, 500 mg/kg diet). The monitored biomarkers included: DNA adducts in bronchoalve olar 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 r ats to smoke resulted in dramatic alterations of all investigated parameter s. N-Acetyl-L-cysteine, phenylethyl isothiocyanate, and 5,6- benzoflavone e xerted a significant protective effect on all alterations. 1,2-Dithiole-3-t hione 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, c ombination of N-acetyl-L-cysteine with Oltipraz was the most potent treatme nt, resulting in an additive or more than additive inhibition of smoke-rela ted DNA adducts in the lung and hemoglobin adducts. These results provide e vidence for the differential ability of test agents to modulate smoke-relat ed biomarkers in the respiratory tract and other body compartments and high light the potential advantages in combining chemopreventive agents working with distinctive mechanisms.