Clinical Phase I Multiple-Dose Safety Research Study of Oltipraz in Smokers

OBJECTIVES:

• Determine the effect of oltipraz on the level of BP-7,8-diol-9,10-epoxide (BPDE) DNA adducts in the lung lining cells (macrophages and bronchial epithelial cells) of smokers.
• Determine the tolerability and toxicity of this treatment regimen in these patients.
• Determine the effect of this treatment regimen on the level of macromolecule adducts in the blood (e.g., BPDE DNA, BPDE hemoglobin, and 8-hydroxy-deoxyguanine), oral lining cells (BPDE DNA), bladder lining cells (4-aminobiphenyl DNA), and lung macrophages (8-hydroxy-deoxyguanine) in these patients.
• Determine the effect of this treatment regimen on the change (decrease) in activation of NNK as measured by change (increase) in urinary NNAL plus NNAL glucuronide in these patients.
• Determine the effect of this treatment regimen on the oxidative state, glutathione-S-transferase activity, and superoxide dismutase 3 and phase II enzymes in the lungs and blood of these patients.
• Compare the changes in oxidative state and phase II enzymes with changes in adduct levels in the lungs and blood of these patients.
• Determine the correlation between oltipraz-induced changes in phase II enzymes and adduct formation with genotypic variation in glutathione-S-transferase isozymes in these patients.
• Compare the response to this treatment regimen in terms of oxidative state, phase II enzymes, and adduct formation in the lungs vs the blood in these patients.

OUTLINE: This is a randomized, double-blind, multicenter study. Patients are stratified according to participating center. Patients are randomized to one of three treatment arms.

• Arm I: Patients receive an oral placebo weekly.
• Arm II: Patients receive low-dose oral oltipraz weekly.
• Arm III: Patients receive high-dose oral oltipraz weekly. Treatment continues for 12 weeks in the absence of unacceptable toxicity.

Patients are followed at 4 weeks.