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SYMPOSIA

Protection Against Oxidative Stress by Nitroxides

James B. Mitchell^*, Murali C. Krishna^*, Periannan Kuppusamy^*,, John A. Cook^* and Angelo Russo^*

^* Radiation Biology Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892 and
Division of Cardiology, Johns Hopkins University, Baltimore, Maryland 21205

Oxidative stress is implicated in the pathogenesis of a variety of human diseases, as well as evoking fundamental genetic responses. The final common pathway in the mechanism of action of ionizing radiation, many chemotherapeutic agents, and immunologic regulation is through oxidizing radical species. Stable nitroxide free radicals have been employed to probe various biophysical and biochemical processes involving oxidative stress. We have demonstrated that nitroxides at non-toxic concentrations are effective as in vitro and in vivo antioxidants when oxidation is induced by superoxide, hydrogen peroxide, organic hydroperoxides, ionizing radiation, or specific DNA-damaging anticancer agents. The protection of oxidative damage in biological systems (both in vitro and in vivo) by non-toxic levels of nitroxides has several plausible chemical explanations: 1) SOD-mimicking action; 2) oxidation of reduced metals that have potential to generate site specific -OH radicals; 3) termination of free radical chain reactions induced by alkyl, alkoxyl, alkylperoxyl radical species, and detoxifying drug-derived radicals; and 4) detoxification of hypervalent toxic metal species such as ferryl and cupryl ions. Examples of the protection of nitroxides against oxidative stress at the cellular and animal level, proposed chemical mechanisms underlying the protective action(s), and the potential use of nitroxides in clinical settings is presented.

Additionally, the application and feasibility of nitroxides and other paramagnetic probes for in vivo Electron Paramagnetic Resonance imaging (EPRI) to study probe uptake, oxygen concentration in tissues, and tissue redox reactivity is discussed. The development of ``functional imaging'' approaches, in addition to providing the physical architecture of a structure, will provide physiological/metabolic information about the structure. EPRI, a magnetic resonance technique similar to Magnetic Resonance imaging, probes the magnetic properties of species containing unpaired electrons (free radicals, transition metals, etc.). With the availability of exogenous, non-toxic, biologically compatible free radical probes, EPRI has the potential to provide, in a non-invasive manner, valuable physiologic information in three dimensions. For example, nitroxides are redox sensitive probes, which are useful to non-invasively delineate tissue heterogeneity such as that occurring between normal and malignant tissue with respect to distribution, redox status, and oxygen concentration. Measurements using spin label oximetry showed significant hypoxia in tumors compared to normal tissue. These results suggest that tumor hypoxia results in more rapid reduction of nitroxides than in normal tissue, which in turn may explain the selective radioprotection of normal tissue by nitroxides.

References

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2. Mitchell JB, Samuni A, Krishna MC, DeGraff WG, Ahn MS, Samuni U, Russo A. Biologically active metal-independent superoxide dismutase mimics. Biochemistry 29:2802–2807, 1990.[Medline]
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4. Krishna MC, Grahame DA, Samuni A, Mitchell JB, Russo A. Oxoarnmonium cation intermediate in the nitroxide-catalyzed dismutation of superoxide. Proc Natl Acad Sci 89:5537–5541, 1992.[Abstract/Free Full Text]
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7. Krishna MC, Samum A, Taira J, Goldstein S, Mitchell JB, Russo A. Stimulation by nitroxides of catalase-like activity of hemeproteins. J Biol Chem 271:26018–26025, 1996.[Abstract/Free Full Text]
8. Hahn SM, Sullivan FJ, DeLuca AM, Krishna MC, Wersto N, Venzon D, Russo A, Mitchell JB. Evaluation of tempol radioprotection in a murine tumor model. Free Radic Blol Med 22:1211–1216, 1997.[Medline]
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10. Kuppusamy P, Afeworki M, Shankar RA, Coffin D, Krishna MC, Hahn SM, Mitchell JB, Zweier JL. In vivo electron paramagnetic resonance imaging of tumor heterogeneity and oxygenation in a murine model. Cancer Res 58:1562–1568, 1998.[Abstract/Free Full Text]

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