Inhibition of mitogen-activated protein kinase activity of human lymphocytes after oral administration of Oltipraz.
Several preclinical studies indicated that Oltipraz appears to be one of the most potent cancer chemopreventive agents. Pharmacological studies in humans provided substantial amounts of information related to doses and schedules. Oltipraz has been reported to induce phase II drug-metabolizing enzymes. However, its chemopreventive activity suggests that it may also interact with cellular processes associated with cancer cell growth and proliferation. During a clinical trial designed to monitor eventual Oltipraz toxicity in high-risk population for development of lung cancer, we performed companion studies related to cell proliferation. Human lymphocytes were chosen as surrogate tissue to assess the in vivo effects of Oltipraz on cell signaling pathways involved in cell proliferation. The results of this study demonstrate that Oltipraz markedly inhibited the activation state of the extracellular signal-regulated kinases of the mitogen-activated protein kinase family of kinases in lymphocytes of subjects treated with two different doses and schedules of Oltipraz. Individual variations were observed that were not related to Oltipraz dosing or schedule of administration. The results from this study indicate that lymphocytes could be used as surrogate tissue for the development of biomarkers for studies of anticarcinogenic agents.
Madhukar
Burra V
BV
Departments of Pediatrics/Human Development, Michigan State University, East Lansing, Michigan 48824-1317, USA.
Dimitrov
Nikolay V
NV
Meyer-Leece
Cheryl
C
Contreras
Margarita L
ML
Crowell
James
J
D000284:Administration, Oral; D000328:Adult; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011719:Pyrazines / Q000008:administration & dosage* / Q000494:pharmacology*; D015398:Signal Transduction; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz