title: Safety and efficacy of weekly oral oltipraz in chronic smokers.
abstract: 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.
authors.affiliation: Department of Medicine, Duke University and Durham Veterans Affairs Hospital, Hematology/Oncology (111G), 508 Fulton Street, Durham, NC 27705, USA. kelleym@duke.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelley
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Glaser
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Frank
authors.initials: F
authors.lastname: Becker
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bhagat
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
authors.forename: Steven G
authors.initials: SG
authors.lastname: Carmella
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
authors.forename: Lilia
authors.initials: L
authors.lastname: Gallot
authors.forename: Lawrence
authors.initials: L
authors.lastname: Schilder
authors.forename: James A
authors.initials: JA
authors.lastname: Crowell
authors.forename: Marjorie
authors.initials: M
authors.lastname: Perloff
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Folz
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Bergan
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011084:Polycyclic Aromatic Hydrocarbons / Q000097:blood*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism; D013871:Thiones; D013876:Thiophenes
chemical_list: D016588:Anticarcinogenic Agents; D011084:Polycyclic Aromatic Hydrocarbons; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C026209:oltipraz