Microbeam Radiation Therapy for Gliomas

描述（由申请人提供）：微束放射治疗（MRT）是一种利用同步加速器产生的平行薄（<100 μ m宽）x射线（微平面束，或微束）的新方法。单组分单向MRT优先杀死实验动物中的胶质瘤，同时保留正常脑组织，因此产生比传统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值）。我们假设MRT的正常组织保留是由于在微光束的直接路径上致命损伤的内皮细胞被在光束之间存活的邻近细胞所取代。本提案将评估上述假设，并检查通过a)剂量分离和b)钆给药可能增强MRT的有益效果。以颅内CNS-1大鼠脑胶质瘤和正常大鼠脑为模型。将微光束的治疗指数与宽光束的治疗指数进行比较。在Aim 1的实验设计中，剂量分级MRT的一个主要考虑因素是，MRT剂量必须间隔1-3周进行分级，足够长的时间（大概）允许血管修复；这种限制的存在是因为第二次辐照的微束模式可能落在第一次辐照的模式之间，从而干扰修复过程。因此，我们将首先进行机制研究来估计正常脑组织的MRT恢复时间，以估计恢复时间。将研究单向非分离（两个等剂量部分，每个部分暂定为非分离剂量的一半）和分离MRT以及非分离宽束。终点将包括正常组织损伤和肿瘤控制，通过MRI，行为测试，生存和组织学评估。目的2，Gd增强MRT的动机是：a)注射MRI造影剂Gadovist后，胶质瘤大量摄取Gd； b) MRT剂量分布的蒙特卡罗模拟表明，在Gd摄取后，肿瘤内微束之间的辐射泄漏（“谷”剂量）增加了三倍。实验包括Gd给药后5分钟单向微束照射和宽束照射。从我们的研究结果中优化高度创新的MRT方法可能会显著提高其治疗指数，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.