Mechanisms of Normal Tissue Toxicity From Irradiation

为了评估正常组织损伤的机制，必须建立足够的体内模型。细胞培养不提供复杂的环境中发现的组织被认为是负责启动辐射损伤。此外，评估晚期毒性的实验通常需要6个月才能确定预期的损伤是否已经发生。在这些实验中，辐射的传递必须精确地定位到目标组织，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评估晚期正常组织毒性的动物项目，通过启动一些动物实验来开发和进一步研究皮肤、肺和肠道的急性和晚期毒性。这涉及到开发专门的放射治疗固定剂和屏蔽剂，以准确地提供预期剂量。我们发现，动物接受的辐射剂量可能会导致可重复的毒性，我们已经收集了样本，以进行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尚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，包括收集胃肠道恶性肿瘤、乳腺癌和前列腺癌放疗患者的各种生物标本。在这项临床试验的背景下，正在测试一些候选的辐射毒性生物标志物。另一项试验完成了测试局部氮氧化物作为减少放射性皮炎的可能方法。这种氮氧化物已经被参与这项试验的辐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，针对它们，并将这些发现转化为临床。在这个项目中已经确定了辐射损伤的几个重要途径，并且以这些途径为目标的药剂已被证明是有效的辐射减缓剂。我们希望将这些发现应用于临床。

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.