It has long been believed that the predominant toxic product of ionizing radiation is the hydroxyl free radical. Its short lifetime makes it extremely difficult to measure. However, the applicants have recently measured radiation induced hydroxyl radical production directly in a murine leg tumor in real time, using a new technique developed in their laboratory. The hydroxyl radical was detected at the site where it evolved with a novel very low frequency electron paramagnetic resonance (EPR) spectroscopy in combination with new, robust in vivo spin trapping techniques. This is a noninvasive technique, which does not involve injury or destruction of the animal/patient subject. These studies, although preliminary, will eventually correlate the evolution of free radicals with the biologic effect of ionizing radiation. This, for example, will allow the applicants to predict that component of radiation effect that can be modulated by scavenging hydroxyl radicals and develop strategies to optimally modulate those radiation effects. The conditions of the initial measurement, however, were extreme. The objective of this grant application is to further develop spin/trapping/low frequency EPR spectroscopy to localize radiation induced hydroxyl radical formation at clinically relevant radiation doses in vivo and in real time in intracellular, interstitial and vascular compartments. The investigators will use this technique to probe thiol protection from radiation damage to further understand basic mechanisms of the biological effect of ionizing radiation in animals.
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