Mechanisms of Normal Tissue Toxicity From Irradiation

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。本实验室 已经建立了一个程序，通过启动 许多动物方案旨在开发和进一步研究急性和晚期毒性， 皮肤肺和肠这涉及到专门辐射的发展 治疗固定器和防护罩，以准确输送预期剂量。动物被 我们发现，用辐射剂量处理， 已经收集了样本用于额外的高通量和假设驱动的工作， 确定已知的和尚未描述的途径的时间激活过程中， 辐射毒性此外，还进行了两项临床试验，NCI 07-C-0111和NCI 07-C-0112。 09-C-0120，包括采集接受 用于胃肠道恶性肿瘤、乳腺癌和前列腺癌的放射治疗。一些 辐射毒性的候选生物标志物正在本临床试验的背景下进行测试。 审判完成了一项额外的试验，测试局部氮氧化物作为一种可能的方法， 减少放射性皮炎。这种氮氧化合物已被广泛研究的辐射 生物学分支的一位专家。该项目的主要目标是 描述与辐射损伤相关的途径，针对它们，并翻译这些发现 去诊所辐射损伤中的几个重要途径已经在 该项目和针对这些途径的药剂已被证明是有效的辐射 缓和剂。我们希望将这些发现转化为临床。

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 effects to confound results. Our laboratory has established a 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 skin, lung, and intestine. This has involved the development of specialized radiation treatment immobilizers and shields to deliver the intended dose accurately. Animals have been treated with doses of radiation that we found could reproducibly result in toxicity and samples have been collected for additional high-throughput and hypothesis-driven work to determine the temporal activation of known and yet undescribed pathways in the process of radiation toxicity. In addition, two clinical trials were conducted, NCI 07-C-0111 and NCI 09-C-0120, that included the collection of various biospecimens in patients receiving radiotherapy for gastrointestinal malignancies, breast cancer, and prostate cancer. A number of candidate biomarkers of radiation toxicity are being tested in the context of this clinical trial. An additional trial was completed testing a topical nitroxide as a possible method to reduce radiation dermatitis. This nitroxide has been studied extensively by the radiation biology branch who is collaborating in this trial. The major goal of this project is to describe pathways associated with radiation injury, target them, and translate these findings to the clinic. Several pathways important in radiation injury have already been identified in this project and agents targeting these pathways have been shown to be effective radiation mitigators. We hope to translate these findings into the clinic.