Phenethyl Isothiocyanate in Preventing Lung Cancer in Smokers

OBJECTIVES:

Primary

- To determine whether oral phenethyl isothiocyanate (PEITC) affects urinary levels of
biomarkers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in
current smokers.

Secondary

- To determine the effect of GSTM1 genotype on PEITC's impact on urinary biomarkers of
NNK metabolism.

- 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
arm I.

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
expression.

Inclusion criteria:

Initial from phone interview:

- Currently smoking 10-45 cigarettes per day for the past year;

- Between the ages of 21 and 70 years;

- In apparently good physical health with no unstable medical conditions including
seizures or cancer;

- In stable and good mental health, i.e., currently do not experience unstable or
untreated psychiatric diagnosis, including substance abuse, as determined by the
DSM-IV criteria, during the past six months;

- Not using any other tobacco or nicotine-containing products;

- Not on methadone maintenance or stimulants such as ephedra; not a regular user of
street drugs and if uses occasionally, willing to abstain during the study; not
taking any drugs known to be P4501A6 substrates such as phenobarbital, rifampicin,
dexamethasone, ketoconazole, methoxsalen, pilocarpine, or tranylcypromine due to
their role in NNK metabolism;

- Does not average more than 21 alcoholic drinks per week;

- Willing to perform study activities such as having blood sample drawn, urine
collection, multiple clinic visits;

- For female subjects of child bearing potential, not known to be pregnant or nursing,
or planning to become pregnant within next 12 months.

For enrollment in the Short-Term Trial:

- Subjects who are generally healthy with liver enzyme and blood count values within
the ranges shown below based on blood samples drawn at the second screening visit.
Specifically:

- White blood cells ≥ 3,000/mL

- Total bilirubin ≤ 1.5 x upper limits of normal (ULN)

- AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN

- BUN and serum creatinine ≤ 1.5 x ULN

For enrollment in the Long-Term Trial:

- Participated in the short-term trial and invited to participate in the long-term
trial;

- Possess the GSTM1 null-null genotype;

- Smoke 20 or more cigarettes/day with a cumulative smoking history of 20 or more
pack-years (one pack-year equals to smoking a pack of cigarettes a day for one year);

- Normal liver enzymes based on blood sample drawn during 1 month wash-out;

- Determined to be a good candidate for the bronchoscopy procedure by a primary care
physician.

Exclusion Criteria:

- Subjects with uncontrolled hypertension, uncontrolled diabetes mellitus, unstable
coronary artery disease, history of cancer other than non-melanoma skin cancer, and
pregnant or lactating women will not be eligible.