Safety and efficacy of weekly oral oltipraz in chronic smokers

Michael J. Kelley, Elizabeth M. Glaser, James E. Herndon, Frank Becker, Rajesh Bhagat, Yu Jing Zhang, Regina M. Santella, Steven G. Carmella, Stephen S. Hecht, Lilia Gallot, Lawrence Schilder, James A. Crowell, Marjorie Perloff, Rodney J. Folz, Raymond Bergan

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)892-899
Number of pages8
JournalCancer Epidemiology Biomarkers and Prevention
Volume14
Issue number4
DOIs
StatePublished - Apr 2005
Externally publishedYes

Fingerprint

Safety
Smoke
Tobacco
Enzymes
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Placebos
Lung
Aflatoxins
DNA Adducts
Polycyclic Aromatic Hydrocarbons
Bronchoalveolar Lavage
Drug-Related Side Effects and Adverse Reactions
Glutathione
Carcinogenesis
Urinary Bladder
Biomarkers
Smoking
Epithelial Cells
oltipraz
Urine

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Safety and efficacy of weekly oral oltipraz in chronic smokers. / Kelley, Michael J.; Glaser, Elizabeth M.; Herndon, James E.; Becker, Frank; Bhagat, Rajesh; Zhang, Yu Jing; Santella, Regina M.; Carmella, Steven G.; Hecht, Stephen S.; Gallot, Lilia; Schilder, Lawrence; Crowell, James A.; Perloff, Marjorie; Folz, Rodney J.; Bergan, Raymond.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 14, No. 4, 04.2005, p. 892-899.

Research output: Contribution to journalArticle

Kelley, MJ, Glaser, EM, Herndon, JE, Becker, F, Bhagat, R, Zhang, YJ, Santella, RM, Carmella, SG, Hecht, SS, Gallot, L, Schilder, L, Crowell, JA, Perloff, M, Folz, RJ & Bergan, R 2005, 'Safety and efficacy of weekly oral oltipraz in chronic smokers', Cancer Epidemiology Biomarkers and Prevention, vol. 14, no. 4, pp. 892-899. https://doi.org/10.1158/1055-9965.EPI-04-0585
Kelley, Michael J. ; Glaser, Elizabeth M. ; Herndon, James E. ; Becker, Frank ; Bhagat, Rajesh ; Zhang, Yu Jing ; Santella, Regina M. ; Carmella, Steven G. ; Hecht, Stephen S. ; Gallot, Lilia ; Schilder, Lawrence ; Crowell, James A. ; Perloff, Marjorie ; Folz, Rodney J. ; Bergan, Raymond. / Safety and efficacy of weekly oral oltipraz in chronic smokers. In: Cancer Epidemiology Biomarkers and Prevention. 2005 ; Vol. 14, No. 4. pp. 892-899.
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