| The goal of the
work proposed in this grant application is
to complete an ongoing randomized, placebo-controlled,
double-blind chemoprevention trial using a
placebo tablet or a tablet containing 200
ug high-selenium brewer’s yeast per
day, given for a duration of six months. Blood,
urine and sputum specimens are being collected
at two baseline time points, and after 3 and
6 months of intervention. Endobronchial biopsies
are obtained at the end of the study. Our
specific aims are stated in the following
questions.
Does selenium supplementation decrease
the frequency of cellular dysplasia detected
in sputum? Sputum dysplasia is an
established risk factor for lung cancer. We
will determine if supplementation with selenium
decreases the incidence of this risk factor
as well as the occurrence of metaplasia/dysplasia
in endobronchial biopsy specimens. Since sensitivity
to detect changes mediated by selenium may
be limited using cellular dysplasia as an
endpoint, we will also determine if selenium
induces changes in the nuclear morphometry
of cells in sputum that are reflective of
changes in lung cancer risk.
Does selenium supplementation decrease
indicators of oxidative cellular damage in
either blood, urine or the lung?
A cascade of complex inflammatory events are
associated with both the malignant and nonmalignant
sequelae of asbestos exposure. Given the protective
role of some selenoproteins in oxidant-mediated
cell damage, our population of asbestos-exposed
individuals is an ideal cohort in which to
directly assess whether selenium decreases
oxidative damage to cellular macromolecules
in individuals that are oxidatively challenged,
and that may have higher nutritional requirements
for antioxidant defense due to oxidative stress.
To evaluate this question, we will measure
several indices of oxidative damage reported
to be elevated in asbestos-exposed individuals.
These markers include 8-hydroxydeoxyguanosine
(8-OHdG) in DNA of lymphocytes isolated from
blood and in urine, malondialdehyde (MDA)
in plasma, sputum, and urine, and 8-iso-prostaglandin
F2 -alpha (8-EPG) in urine. Levels of these
indices will be determined at baseline (both
visits) and after 3 and 6 months of selenium
supplementation. In addition we will determine
the degree of cellular DNA damage in pulmonary
epithelial cells from endobronchial biopsy
and sputum using the comet assay (in the presence
and absence of endonuclease III or FPG), a
single cell gel electrophoresis assay that
detects DNA strand breaks as well as oxidative
damage to purines and pyrimidines. This project
will contribute to understanding whether intermediate
biomarkers for lung cancer can be altered
by selenium, a finding of potential clinical
and public health importance. This study will
also establish whether selenium has any effect
on nuclear morphometry, a promising new cytological
marker of lung cancer risk. Furthermore, our
study addresses the question of whether the
much-discussed antioxidant activity of selenium
is a relevant mechanism of chemopreventive
action.
|
