Mechanisms of Normal Tissue Toxicity From Irradiation

为了评价正常组织损伤的机制，必须建立适当的体内模型。细胞培养不提供在被认为是引起辐射损伤的组织中发现的复杂环境。此外，评估晚期毒性的实验通常需要6个月来确定是否发生了预期的损伤。这些实验的辐射输送必须精确地定位到感兴趣的组织，以防止可能的外围效应混淆结果。我们的实验室已经建立了一个动物计划，通过启动一些动物方案，旨在开发和进一步研究皮肤，肺和肠道的急性和晚期毒性，评价晚期正常组织毒性。这涉及开发专门的放射治疗固定器和防护罩，以准确地输送预期剂量。动物已经用我们发现可以重复导致毒性的剂量的辐射进行了治疗，并且已经收集了样品用于额外的高通量和假设驱动的工作，以确定辐射毒性过程中已知但未描述的途径的时间激活。此外，还进行了两项临床试验，NCI 07-C-0111和NCI 09-C-0120，包括在接受胃肠恶性肿瘤、乳腺癌和前列腺癌放疗的患者中采集各种生物标本。在本临床试验的背景下，正在测试一些辐射毒性的候选生物标志物。完成了一项额外的试验，测试局部氮氧化物作为减少放射性皮炎的可能方法。这个氮氧化合物已经被参与这项试验的放射生物学分支广泛研究。该项目的主要目标是描述与辐射损伤相关的途径，靶向它们，并将这些发现转化为临床。本项目已经确定了辐射损伤的几个重要途径，靶向这些途径的药物已被证明是有效的辐射缓解剂。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 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 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.