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Supplement: Free Radicals: The Pros and Cons of Antioxidants

Novel Functional Imaging for Tissue Oxygen Concentration and Redox Status¹

Radiation Biology Branch, National Cancer Institute, Bethesda, MD 20892

²To whom correspondence should be addressed. E-mail: jbm{at}helix.nih.gov.

KEY WORDS: • functional imaging • hypoxia • redox imaging • electron paramagnetic resonance imaging

	EXPANDED ABSTRACT

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The hypothesis that regions of hypoxia within human tumors would limit the effectiveness of radiotherapy was made nearly 50 years ago. Likewise, hypoxia could present a problem for systemic forms of therapy such as chemotherapy because of compromised delivery of the drug to the tumor cells. However, only over the past 15 years have sufficient data accumulated regarding human tumor oxygenation status using oxygen electrodes to assess its importance. Oxygen electrode data have shown that some (not all) human tumors do indeed contain hypoxic regions, the extent of hypoxia can influence tumor response to radiation treatment, and the presence of hypoxia is an indicator of tumor aggressiveness (1). These findings point to the importance of a priori knowledge of pO₂ levels in tumors to select the most appropriate and effective treatment options.

Emerging developments in MRI add a functional and/or physiological dimension to anatomical images. Noninvasive imaging techniques currently are under development to provide tissue oxygen concentration and redox status information. Such technologies have the potential to aid physicians before, during, and after a course of therapy to prognosticate tumor and normal tissue biology, predict response to therapy, and guide therapeutic strategy throughout treatment. Overhauser MRI (OMRI) utilizes the enhancement of proton MRI images by a nontoxic free radical contrast agent. The advantages of this technique are the very low magnetic fields employed and its capability to provide quantitative information of tissue oxygen concentration (2). Using OMRI, we demonstrated recently that spatially resolved oxygen levels in a 1-cm diameter SCCVII mouse tumor are heterogeneous, with regions of hypoxia (<10 mm Hg) (3). The spatial and temporal resolution was 1 mm and 2 min, respectively. Oxygenation of tumors was enhanced upon carbogen inhalation. The oxygen measurements from OMRI were in agreement with those obtained by independent polarographic measurements using an Eppendorf oxygen electrode.

Tissue redox studies are performed using electron paramagnetic resonance imaging (EPRI), where the rate of nitroxide (free radical spin probe) reduction to the EPRI silent hydroxylamine is recorded spatially and reconstructed into a "tissue redox map" (4–6). We have recently shown that the redox map of SCCVII tumors is heterogeneous and that depletion of cellular glutathione in SCCVII tumors yields decreased nitroxide reduction capability and a shift in the redox map (4). Both OMRI and EPRI are promising noninvasive imaging technologies that can be used to better understand tumor and normal tissue physiology and perhaps better define conditions involving oxidative stress.

	FOOTNOTES

 
¹ Presented as part of the conference "Free Radicals: The Pros and Cons of Antioxidants," held June 26–27 in Bethesda, MD. This conference was sponsored by the Division of Cancer Prevention (DCP) and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Department of Health and Human Services (DHHS); the National Center for Complementary and Alternative Medicine (NCCAM), NIH, DHHS; the Office of Dietary Supplements (ODS), NIH, DHHS; the American Society for Nutritional Science; and the American Institute for Cancer Research and supported by the DCP, NCCAM, and ODS. Guest editors for the supplement publication were Harold E. Seifried, National Cancer Institute, NIH; Barbara Sorkin, NCCAM, NIH; and Rebecca Costello, ODS, NIH.

	LITERATURE CITED

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1. Hockel, M., Schlenger, K., Aral, B., Mitze, M., Schaffer, U. & Vaupel, P. (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56:4509-4515.[Abstract/Free Full Text]

2. Golman, K., Leunbach, I., Ardenkjaer-Larsen, J. H., Ehnholm, G. J., Wistrand, L. G., Petersson, J. S., Jarvi, A. & Vahasalo, S. (1998) Overhauser-enhanced MR imaging (OMRI). Acta Radiol. 39:10-17.[Medline]

3. Krishna, M. C., English, S., Yamada, K., Yoo, J., Murugesan, R., Devasahayam, N., Cook, J. A., Golman, K. & Ardenkjaer-Larsen, J. H., et al (2002) Overhauser enhanced magnetic resonance imaging for tumor oximetry: coregistration of tumor anatomy and tissue oxygen concentration. Proc. Natl. Acad. Sci. 99:2216-2221.[Abstract/Free Full Text]

4. Kuppusamy, P., Li, H., Ilangovan, G., Cardounci, A. J., Zweier, J. L., Yamada, K., Krishna, M. C. & Mitchell, J. B. (2002) Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. Cancer Res 62:307-312.[Abstract/Free Full Text]

5. Yamada, K. I., Kuppusamy, P., English, S., Yoo, J., Irie, A., Subramanian, S., Mitchell, J. B. & Krishna, M. C. (2002) Feasibility and assessment of non-invasive in vivo redox status using electron paramagnetic resonance imaging. Acta Radiol 43:433-440.[Medline]

6. Ilangovan, G., Li, H., Zweier, J. L., Krishna, M. C., Mitchell, J. B. & Kuppasamy, P. (2002) In vivo measurement of regional oxygenation and imaging of redox status in RIF-1 murine tumor: effect of carbogen-breathing. Magn. Reson. Med. 48:723-730.[Medline]

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