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.
| Gottschall, E Brigitte; McGinley, John N; Spoelstra, Nicole et al. (2005) Effect of cytological fixative and environmental conditions on nuclear morphometric characteristics of squamous epithelial cells in sputum. Cytometry B Clin Cytom 67:19-26 |
| Gottschall, E Brigitte; Wolfe, Pam; Haegele, Albert D et al. (2004) Increased urinary 8-isoprostaglandin F(2)alpha is associated with lower plasma selenium levels and lower vegetable and fruit intake in an asbestos-exposed cohort at risk for lung cancer. Chest 125:83S |
