Microbeam Radiation Therapy for Gliomas

描述（由申请人提供）：微束放射治疗（MRT）是一种新的方法，它利用同步加速器产生的X射线（微平面束或微束）的平行、薄（<100 μ m宽）平面。单次单向MRT优先杀死实验动物中的胶质瘤，同时保留正常脑组织，从而产生比常规宽束治疗更高的治疗指数（正常组织耐受的最大剂量与消融肿瘤的最小剂量的比率）。我们假设，正常组织保留的MRT是由于致命损伤的内皮细胞的直接路径的微束之间的生存的相邻细胞的替代。本提案将评估上述假设，并通过a）剂量分次和B）钆给药检查MRT有益作用的可能增强。将颅内CNS-1大鼠胶质瘤和正常大鼠脑用作模型。将微束的治疗指数与宽束的治疗指数进行比较。目标1的实验设计中的一个主要考虑因素，剂量分级MRT，是MRT剂量必须以间隔，1-3周，足够长的时间来允许（大概）血管修复;存在这种限制，因为来自第二次照射的微束模式可能落在来自第一次照射的模式之间，从而干扰修复过程。因此，将首先进行估计正常脑组织从MRT恢复时间的机制研究，以估计恢复时间。将研究单向未分割（两个相等的剂量部分，每个部分暂定为未分割剂量的一半）和分割MRT以及未分割宽射束。终点将包括通过MRI、行为测试、存活率和组织学评估的正常组织损伤和肿瘤控制。目的2，Gd增强MRT，是由以下因素激发的：a）注射MRI造影剂Gadovist后胶质瘤对Gd的大量摄取，和，B）MRT剂量分布的Monte Carlo模拟，表明肿瘤中微束之间的辐射泄漏（“谷”剂量）在Gd摄取后增加三倍。实验将包括Gd给药后5分钟的单向微束和宽束照射。从我们的研究结果中优化MRT的高度创新方法可能会显着提高其治疗指数，从而导致脑肿瘤放射治疗的突破。

DESCRIPTION (provided by applicant): Microbeam Radiation Therapy (MRT) is a novel approach that utilizes parallel, thin (<100 mum wide) planes of synchrotron-generated x-rays (microplanar beams, or microbeams). Single-fraction unidirectional MRT preferentially kills gliomas in experimental animals while sparing normal brain tissue, thus producing a higher therapeutic index (ratio of maximum dose tolerated by normal tissue to the minimum dose ablating the tumor) than conventional broad-beam therapy. We hypothesize that the normal-tissue-sparing of MRT is due to the replacement of lethally injured endothelial cells in the direct paths of the microbeams by their neighboring cells surviving between the beams. This proposal will evaluate the above hypothesis, and examine possible enhancement of the MRT's beneficial effects by a) dose-fractionation, and b) by gadolinium administration. Intracranial CNS-1 rat glioma and the normal rat brain will be used as models. Microbeams' therapeutic index will be compared to that of broad beams. A major consideration in the experimental design of Aim 1, dose-fractionated MRT, is that MRT dose must be fractionated at intervals, 1-3 weeks, long enough to permit (presumably) vascular repair; this limitation exists because the microbeam pattern from the second irradiation may fall between the pattern from the first one, thus interfering with the repair process. Therefore, mechanistic studies to estimate the recovery time of normal brain tissue from MRT will be pursued first to estimate the recovery time. Unidirectional unfractionated (two equal dose fractions, each tentatively half the unfractionated dose) and fractionated MRT, as well as unfractionated broad beams will be studied. The endpoints will include normal-tissue damage and tumor control assessed by MRI, behavioral tests, survival, and histology. Aim 2, Gd-enhance MRT, is motivated by a) the large uptake of Gd by the glioma after injecting the MRI contrast agent, Gadovist, and, b) Monte Carlo simulations of MRT dose distribution demonstrating that the tumor's the radiation leakage between microbeams (the "valley" dose) in the tumor increases three-fold after Gd uptake. Experiments will include unidirectional microbeam and broad-beam irradiations 5 minutes after Gd administration. Optimizing the highly innovative method of MRT from our findings may significantly boost its therapeutic index, leading to a breakthrough in the radiation therapy of brain tumors.