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Noninvasive Imaging of Tumor Redox Status and Its Modification by Tissue Glutathione Levels¹

The EPR Center and Division of Cardiology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21224 [P. K., H. L., G. I., A. J. C., J. L. Z.], and Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [K. Y., M. C. K., J. B. M.]

Therapeutic regimens such as radiation or chemotherapy attempt to exploit the physiological differences between normal and malignant tissue. Tissue redox status and pO₂ are two factors that are hypothesized to be different in normal and malignant tissues. Methods that can detect subtle differences in the above physiological parameters would greatly aid in devising appropriate treatment strategies. We have previously used in vivo electron paramagnetic resonance (EPR) spectroscopy and imaging techniques and shown that tumor tissues are highly reducing and hypoxic compared with normal tissues (P. Kuppusamy et al., Cancer Res., 58: 1562–1568, 1998). The purpose of the present study was to obtain spatially resolved redox data from normal and tumor tissues of radiation-induced fibrosarcoma (RIF-1) tumor-bearing mice and to examine the role of intracellular glutathione (GSH) on the tissue redox status. Experiments were performed using low-frequency (1.3 GHz) in vivo EPR spectroscopy and imaging techniques with a nitroxide redox probe. L-buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH synthesis, was used to deplete tissue GSH levels. The results show the existence of significant heterogeneity of redox status in the tumor tissue compared with normal tissue. The tumor tissues show at least 4-fold higher concentrations of GSH levels compared with normal tissues in the tumor-bearing mice. Also BSO treatment showed a differential depletion of GSH and reducing equivalents in the tumor tissue. Thus, it appears that there is significant heterogeneity of tumor redox status and that manipulation of the tumor redox status may be important in tumor growth and therapy.

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