Randomized Trial of PEITC as a Modifier of NNK Metabolism in Smokers
- To determine whether oral phenethyl isothiocyanate (PEITC) affects urinary levels of
biomarkers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in
- To determine the effect of GSTM1 genotype on PEITC's impact on urinary biomarkers of
- To determine the effect of GSTM1 genotype on the metabolism and excretion of PEITC as
measured by urinary levels of its major metabolite.
- To determine whether oral PEITC affects molecular markers of cell proliferation (Ki-67)
and apoptosis (caspase-3 and TUNEL) in bronchial tissue.
OUTLINE: Patients are stratified according to GST genotypes (GSTM1 null-null genotype vs
GSTM1-positive genotype). All participants are initially enrolled in the short-term trial.
After the completion of the short-term trial, only those participants meeting certain
criteria may proceed to the long-term trial.
- Short-term trial: Participants are randomized to 1 of 2 treatment arms.
- Arm I: Participants are asked to smoke only deuterated NNK cigarettes (provided by
the study) and record the exact number of cigarettes smoked and alcoholic drinks
consumed each day for 1 month. Participants receive oral phenethyl isothiocyanate
(PEITC) four times daily for 5 days in week 2 and oral placebo four times daily
for 5 days in week 4. Participants keep a diary of all food and beverages consumed
on the days that PEITC or placebo are taken.
- Arm II: Participants receive oral placebo four times daily for 5 days in week 2
and oral PEITC four times daily for 5 days in week 4. Participants are also asked
to smoke only deuterated NNK cigarettes, record the number of cigarettes smoked
and alcoholic drinks consumed each day, and keep a food and beverage diary as in
After completion of the short-term trial, participants undergo a wash-out period for 1 month
in which they are asked to resume smoking regular cigarettes. Participants are offered
smoking cessation assistance, if desired. Only those participants meeting certain criteria
may proceed to the long-term trial after the 1-month wash-out period.
- Long-term trial: Participants are randomized to 1 of 2 treatment arms.
- Arm I: Participants receive oral PEITC twice daily for 12 months.
- Arm II: Participants receive oral placebo twice daily for 12 months. Participants
in both arms complete a 3-day food diary monthly for 12 months and a
food-frequency questionnaire at baseline and at the completion of study treatment.
All participants undergo blood and urine sample collection periodically for laboratory
studies. Participants enrolled in the long-term trial also undergo bronchoscopy and tissue
biopsy at baseline and at the completion study treatment. Urine samples are examined by
liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) for
various biomarkers. Tissue samples are examined by IHC for Ki-67, TUNEL, and caspase-3
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention
Urinary levels of biomarkers of NNK metabolism
Total NNAL, free NNAL, keto acid and hydroxyacids will be measured by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS).
Baseline and Completion of Study Treatment
Jian-Min Yuan, PhD
Masonic Cancer Center, University of Minnesota
United States: Food and Drug Administration
|Masonic Cancer Center, University of Minnesota||Minneapolis, Minnesota 55455|