Mechanisms of Normal Tissue Toxicity

为了评估正常组织损伤的机制，必须建立适当的体内模型， 发展。细胞培养不提供组织中存在的复杂环境 被认为是引发辐射损伤的原因。此外，实验 评估晚期毒性通常需要6个月的时间来确定预期的损伤是否已经 发生了。这些实验的辐射输送必须精确地定位在 目的组织，以防止可能的外周效应混淆结果。今年 一个实验室已经建立了一个评估晚期正常组织毒性的动物程序 通过启动一些动物方案，旨在开发和进一步研究急性 以及食道、肺、肠和肌肉中的晚期毒性。这涉及到 开发专门的放射治疗固定器和防护罩， 准确的预期剂量。最初的测试剂量已经交付，动物正在 随后评估是否出现预期毒性。随后将进行大规模的 在每个正常组织部位中进行实验，在此期间，组织、尿液和血浆将被 收集，以便进行各种测试。这些机械实验将需要一个 对组织标本、血浆和尿液（包括微阵列）的大量工作， 激光捕获显微切割、免疫组织化学、Western印迹、ELISA和RT-PCR。一 已经获得了这些测定所需的各种一次性用品和设备。在 此外，一项临床试验已经启动，NCI 07-C-0111，这将允许收集 各种生物标本在接受放射治疗的胃肠道恶性肿瘤患者。 将在此背景下测试一些辐射毒性的候选生物标志物。 临床试验

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.