Cigarette smoking is thought to contribute to
carcinogenesis by formation of
DNA adducts of tobacco
smoke constituents leading to genotoxic damage. The dithiolethione,
oltipraz, is a putative
cancer chemopreventive agent that induces phase II detoxifying
enzymes in preclinical models and reduces
aflatoxin adducts in humans living in areas with high dietary levels. To determine if
oltipraz could reduce adduct levels of tobacco
smoke constituents in the lungs and other target organs, chronic smokers were enrolled to one of three arms: 400 or 200 mg/wk oral
oltipraz or placebo. Endobronchial tissue and bronchoalveolar lavage were done before and after 12 weeks of drug treatment; peripheral blood, urine, and oral saline rinse were also collected. Toxicity was assessed every 4 weeks. Fifty-nine of the 77 enrolled subjects completed the study. Of those receiving
oltipraz, 15% experienced grade 2/3 toxicity, which was predominantly gastrointestinal. All subject withdrawals occurred in the
oltipraz groups. There was no significant difference between pre- and post-
polycyclic aromatic hydrocarbon-
DNA adduct levels in lung epithelial cells measured by immunoperoxidase staining between treatment and placebo groups. Likewise, no significant differences were found in
polycyclic aromatic hydrocarbon or benzo(a)pyrene-7,8-diol-9,10-epoxide adducts measured in blood, oral lining cells, or bladder lining cells. There was also no increase in
mRNA or enzymatic activity of phase II
enzymes and no change in
glutathione levels. Thus, despite moderate drug-related toxicity, there was no significant effect on pharmacodynamic or surrogate risk
biomarkers. Other agents with lower toxicity and greater activity to induce phase II
enzymes are needed to definitively test the detoxification-induction paradigm in smokers.