Radiobiology Investigations of Ions Heavier than Protons

描述（由申请人提供）：带电粒子束（例如质子）对于癌症治疗是有利的，因为粒子的有限范围导致在患者身体表面处的相对小的剂量，而就在粒子停留在组织中（布拉格峰）之前沉积更大的剂量。由于这种剂量分布的优势，近年来质子在癌症治疗中的应用大大扩展。除了物理剂量分布之外，比质子重的离子还具有增加的生物学优势，因为在复制细胞中，通过细胞周期更大的细胞杀伤、降低的氧效应和更小的辐射敏感性变化。这些生物学优势中的许多最初是在美国证明的，重离子的早期临床研究也是在美国进行的。这一知识导致了五个碳离子治疗中心在海外的发展，但在美国没有。重要的是，许多关键的生物学和物理学问题仍然与用于治疗的粒子有关，这种数据的缺乏是充分利用带电粒子治疗潜力的重大障碍。预计在不久的将来， 比质子重的核武器将在美国复活，本文提出了基础辐射生物学研究，这将提供指导此类设施研发所需的新数据。拟议的研究将利用布鲁克海文国家实验室（BNL）的NASA空间辐射实验室（NSRL）的独特设施，该实验室目前是美国唯一可以进行比质子重的离子生物学研究的地方，以进行特定的，高度临床相关的尖端研究。总体目标是解决碳是否是使用粒子进行癌症治疗的最佳离子种类，以及应该使用哪些肿瘤特征来识别从离子治疗中获益最多的肿瘤。具体目标是：（1）确定几种离子种类的生物有效性（2）评估细胞死亡的模式，所述细胞死亡的模式与200 MeV质子相比作为组织等效材料中的深度的函数，用于选择不同辐射响应性的肿瘤和正常细胞类型;（细胞凋亡、永久性细胞周期停滞、有丝分裂灾难、自噬）。我们将检验这样的假设，即重离子诱导的细胞杀伤对以下细胞类型的更大有效性， 在低LET辐射后显示出更大的细胞恢复（即，低剂量/剂量比）是由于在通常对低LET辐射诱导的细胞凋亡具有抗性的细胞中细胞凋亡诱导增加所致。这项系统性研究将提供关于哪种离子种类可能对治疗最有用的新信息，增加对哪种特定肿瘤类型可能最好用特定离子治疗的了解，并提供定量数据以促进用于治疗的离子束的新生物物理建模。这些信息将有助于指导比质子重的设施的规划 美方

DESCRIPTION (provided by applicant): Charged particle beams, such as protons, are advantageous for cancer therapy because the finite range of the particles results in relatively little dose at the surface of a patient's body while depositing greater dose just before the particles come to rest in tissue (the Bragg peak). Because of this dose distribution advantage, the use of protons in cancer treatment has expanded greatly in recent years. In addition to the physical dose distribution, ions heavier than protons have increased biological advantages because of greater cell killing, decreased oxygen effect and smaller variation in radiation sensitivity through the cell cycle in replicating cells. Many of these biological advantages were demonstrated originally in the US and the early clinical studies of heavy ions were in the US. This knowledge led to development of five carbon ion therapy centers overseas, but there are none in the US. Importantly, many critical biology and physics questions remain about particles for therapy use, and this paucity of data is a significant impediment to exploiting the full potental of charged particle therapy. In anticipation that, in the not-too-distant future, therapy with ions heavier than protons will be resurrected in the US, fundamental radiation biology studies are proposed herein that will provide new data needed to guide R&D for such a facility. The proposed studies will utilize the unique facilities at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), currently the only location in the US where biological studies with ions heavier than protons can be conducted, to perform specific, highly clinically-relevant, cutting-edge studies. The overall goal is to address whether carbon is the optimal ion species for cancer therapy with particles and what tumor characteristics should be used to identify the tumors that would benefit most from ion therapy. The specific aims are to: (1) determine biological effectiveness of several ion species (atomic numbers from helium to oxygen) of clinical interest compared to 200 MeV protons as a function of depth in tissue equivalent material for selected tumor and normal cell types of varying radiation responsiveness and (2) assess the mode of cell death (apoptosis, permanent cell cycle arrest, mitotic catastrophe, autophagy) in cells irradiated with heavier ions compared to protons. We will test the hypothesis that the greater effectiveness of heavy ion-induced cell killing for cell types that show greater cell recovery after low LET radiations (i.e., low ¿/¿ ratios) results from increased induction of apoptosis in cells that are normally resistant to low LET-radiation-induced apoptosis. This systematic study will provide novel information on which ion species might be most useful for therapy, increase insight into which specific tumor types might be best treated with specific ions, and provide quantitative data to facilitate novel biophysical modeling of ion beams for therapy. This information will help guide planning for a heavier-than-protons facility in the US.