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Noninvasive In vivo Detection of Glutathione Metabolism in Tumors

¹ Department of Neuroscience, McKnight Brain Institute, and ² Department of Medicine, University of Florida, Gainesville, Florida; ³ Department of Biomedical Engineering, University of North Carolina, Chapel Hill, North Carolina; Departments of ⁴ Medicine, Division of Medical Oncology, and ⁵ Radiation Oncology, Duke University Medical Center, Durham, North Carolina; and ⁶ National High Magnetic Field Laboratory, Tallahassee, Florida

Requests for reprints: Michael P. Gamcsik, Duke University Medical Center, Box 2638, MSRB 395, Research Drive, Durham, NC 27710. Phone: 919-681-2244; Fax: 919-668-3925; E-mail: michael.gamcsik{at}duke.edu.

Magnetic resonance spectroscopic imaging has been used to follow glutathione metabolism and evaluate glutathione heterogeneity in intact tumor tissue. Stable isotope-labeled glutathione was detected in s.c. implanted fibrosarcoma tumors in anesthetized rats following infusion of [2-¹³C]glycine. Using ¹H-decoupled ¹³C magnetic resonance spectroscopy, the appearance of [2-¹³C]glycine at 42.4 ppm and the subsequent incorporation of this isotope label into the glycyl residue of glutathione at 44.2 ppm can be detected. The identity and relative concentrations of labeled metabolites observed in the in vivo spectrum were confirmed in studies of tissue extracts. The high level of isotopic enrichment and the concentration of glutathione in tumor tissue allow for collection of spatially localized spectra using ¹³C chemical shift imaging methods. These data provide the first direct images of glutathione in intact tumor tissue and show metabolic heterogeneity. This method may lead to the ability to monitor changes in tumor tissue redox state that may ultimately affect diagnosis, monitoring, and treatment.