Mechanisms of Normal Tissue Toxicity

为了评估正常组织损伤的机制，必须建立合适的活体模型。细胞培养不提供在组织中发现的复杂环境，这些组织被认为是引发辐射损伤的原因。此外，评估晚期毒性的实验通常需要6个月的时间来确定预期的伤害是否已经发生。这些实验的辐射传输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来开发和进一步研究食道、肺、肠和肌肉的急性和晚期毒性。这涉及到开发专门的放射治疗固定器和防护罩，以准确地提供预期的剂量。我们已经用我们发现可能会重复导致毒性的辐射剂量对动物进行了治疗，并收集了样本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和尚未描述的途径的时间激活。此外，已经启动了两项临床试验，NCI 07-C-0111和NCI 09-C-0120，将允许在接受胃肠道恶性肿瘤、乳腺癌和前列腺癌放射治疗的患者中收集各种生物检疫药物。一些辐射毒性的候选生物标记物将在这项临床试验的背景下进行测试。最近又开始了另一项试验，测试一种局部使用的尼罗酮，作为一种可能的减少放射性皮炎的方法。参与这项试验的辐射生物学分部对这种氮氧化物进行了广泛的研究。该项目还开发了一条新的研究路线，涉及使用骨髓基质细胞来减轻辐射损伤。我们计划在未来几年内进一步发展这一项目，以更好地了解减轻辐射损伤的机制、最佳传递技术以及导致这些影响的分子相互作用。

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 esophagus, lung, intestine, and muscle. 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 have been initiated, NCI 07-C-0111 and NCI 09-C-0120, that will allow 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 will be tested in the context of this clinical trial. An additional trial has recently been opened testing a topical nirtoxide as a posible method to reduce radiation dermatitis. This nitroxide has been studied extensively by the radiation biology branch who is collaborating in this trial. A new line of research has also been developed in this project which involves the use of bone marow stromal cells to mitigate radaition injury. We plan to further develop this project int he coming years to understand better the mechanism of mitigation of radiation injury, optimal delivery techniques, and the molecular interactions responsible for these effects.