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Differential Radiation Protection of Salivary Glands versus Tumor by Tempol with Accompanying Tissue Assessment of Tempol by Magnetic Resonance Imaging

Authors' Affiliations: ¹ Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research and ² Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Ana P. Cotrim, Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Building 10, Room 1N113, MSC-1190, Bethesda, MD 20892. Phone: 301-451-7956; Fax: 301-402-1228; E-mail: acotrim{at}nidcr.nih.gov.

Purpose: The nitroxide free radical, Tempol, was evaluated for potential differential radiation protection of salivary glands and tumor using fractionated radiation. Mechanistic information was explored by monitoring the presence and bioreduction of Tempol in both tissues noninvasively by magnetic resonance imaging (MRI).

Experimental Design: Female C3H mice were immobilized using custom-made Lucite jigs for localized irradiation (five daily fractions) either to the oral cavity or tumor-bearing leg. Tempol (275 mg/kg) was administered (i.p.) 10 min before each radiation fraction. Salivary gland damage was assessed 8 weeks after radiation by measuring pilocarpine-mediated saliva output. Tumor growth was assessed by standard radiation regrowth methods. Dynamic T₁-weighted magnetic resonance scans were acquired before and after Tempol injection using a 4.7T animal MRI instrument.

Results: Tempol treatment was found to protect salivary glands significantly against radiation damage (60% improvement); whereas no tumor protection was observed. Intracellular reduction of Tempol to the nonradioprotective hydroxylamine as assessed by MRI was 2-fold faster in tumor compared with salivary glands or muscle.

Conclusions: Tempol provided salivary gland radioprotection and did not protect tumor, consistent with the hypothesis that differential radioprotection by Tempol resides in faster reduction to the nonradioprotective hydroxylamine in tumor compared with normal tissues. The unique paramagnetic properties of Tempol afforded noninvasive MRI monitoring of dynamic changes of Tempol levels in tissue to support the finding. These data support further development and consideration of Tempol for human clinical trials as a selective protector against radiation-induced salivary gland damage.