Glutathione is a tripeptide normally found in high concentration in normal tissue and frequently elevated in tumor tissue. Glutathione and its oxidized disulfide form the primary reduction/oxidation (redox) buffer in cells. The redox balance in the cell controls gene expression, cell differentiation, proliferation and apoptosis and, therefore, it is not surprising that this balance may be elevated in cancer. In normal tissue glutathione protects the cell from toxicants and the cancer cell has adapted this defense mechanism to shield cells from the effects of anticancer therapies. This results in further elevations in glutathione metabolism in therapy-resistant tumors. Therefore, the accurate determination of glutathione in extracts from normal and tumor tissue has proven to be invaluable to predicting therapy response in patients. This proposal outlines the development of magnetic resonance imaging (MRI) methods to non-invasively monitor glutathione metabolism in normal and tumor tissue. Several MRI methods will be evaluated including the use of 1H-editing, 2H NMR and 13C-chemical shift imaging. Using the most sensitive method, in vivo images of glutathione content obtained from 9L glioma tumors implanted in the flank of rats will be compared to the concentrations measured biochemically in tissue extracts. All of the imaging modalities will measure static glutathione and require the use of stable isotope incorporation. Isotope incorporation-based methods also allow monitoring of the rate of glutathione metabolism in tissue. These types of dynamic studies may be as important as measuring static glutathione levels to stage tumors and predict therapy response. Due to the unique role played by glutathione in cell proliferation, differentiation and apoptosis, the non-invasive monitoring of glutathione metabolism would offer novel diagnostic and prognostic information on the tumor tissue.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA097871-02
Application #
6647110
Study Section
Special Emphasis Panel (ZRG1-SSS-7 (11))
Program Officer
Liu, Guoying
Project Start
2002-08-16
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$157,940
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Thelwall, Peter E; Yemin, Avner Y; Gillian, Theresa L et al. (2005) Noninvasive in vivo detection of glutathione metabolism in tumors. Cancer Res 65:10149-53
Gamcsik, Michael P; Bierbryer, Ross G; Millis, Kevin K (2004) Noninvasive monitoring of glutathione turnover in perfused MCF-7 cells. Free Radic Biol Med 37:961-8