Mechanisms of Normal Tissue Toxicity

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In order to evaluate mechanisms of normal tissue injury, adequate in vivo models must be developed. Cell culture does not provide the complex environment that is found in tissues thought to be responsible for the initiation of radiation injury. In addition, experiments assessing late toxicity often require 6 months to determine if the expected injury has occurred. The delivery of radiation with these experiments must be precisely localized to the tissue of interest to prevent possible peripheral effect to confound results. This year the laboratory has established an animal program for evaluation of late normal tissue toxicity through initiation of a number of animal protocols designed to develop and further study acute and late toxicity in the esophagus, lung, intestine, and muscle. This has involved the development of specialized radiation treatment immobilizers and shields to deliver the intended dose accurately. Initial test doses have been delivered and animals are being followed to evaluate if the expected toxicity develops. This will be followed by a large-scale experiment in each of the normal tissue sites during which tissue, urine, and plasma will be collected to allow for a variety of testing. These mechanistic experiments will require a significant amount of work with tissue specimens, plasma, and urine including microarray, laser capture microdissection, immunohistochemistry, Western blotting, ELISA, and RT-PCR. A variety of disposables and equipment necessary for these assays has been obtained. In addition, a clinical trial has been initiated, NCI 07-C-0111, that will allow the collection of various biospecimens in patients receiving radiotherapy for gastrointestinal malignancies. A number of candidate biomarkers of radiation toxicity will be tested in the context of this clinical trial.