中低能质子致DNA损伤响应的LET相关性研究

Malignant tumor is a serious disease threatening people's health in China. Nowadays it is difficult using conventional therapy to control its mortality. In the world, proton therapy has grown in importance as a modality for cancer treatment in part because of its ability to much more damage to tumor, less harm to normal tissues as compared to conventional radiation. It can greatly improve the cure rate of tumors, which cannot be cured by conventional methods. Development and popularization of proton therapy technology has become extremely urgent for our country. The relative biological effectiveness (RBE) of protons is usually considered similar to the photons in proton treatment planning by assuming a fixed RBE of 1.1. However, recent data suggests that, for several end points of clinical relevance, the biological response is differentially induced by protons compared to photons. Therefore, it is necessary to re-discuss its physical and biological mechanism. In present study, using protons with middle- and low- energy generated by 100MeV cyclotron and HI-13 tandem accelerator, experimental technologies around proton therapy, including beam regulations, diagnostics and dose measurement will be established. By using a radioresistance tumor cells as subject, the dependence of cell response on linear energy transfer (LET) of proton (Bragg peak, plateau) will be investigated, and the correlation of proton energy deposition and DNA double strand breaks spatial distribution will be discussed. All these studies will lay the technology foundation for future cancer therapy of 100MeV proton cyclotron at China Institute of Atomic Energy, and provide the necessary basic data and scientific basis for proton beam therapy.

恶性肿瘤是威胁我国人民健康的重大疾病。当前使用常规疗法已很难控制其死亡率。质子治疗由于具有对肿瘤细胞杀伤大、对正常组织伤害小的优点，已成为国际上治疗肿瘤的重要物理疗法之一，可大大提高常规方法治疗无效的肿瘤的治愈率。在我国发展和普及该项技术已极为迫切。在质子治疗计划中，通常认为其相对生物学效应（RBE）值与光子近似并固定为1.1。但是，最近的数据显示，对临床关心的几个生物学终点来说，质子诱发的生物学响应与光子并不相同。因此，有必要重新讨论其物理和生物学机制。本项目拟利用回旋和串列加速器产生的中低能质子，建立与治疗相关的中能质子束流调节、诊断和剂量测量实验技术。以放射抗拒人类肿瘤细胞为对象，研究细胞响应对质子峰、坪区传能线密度（LET）的依赖性，探讨质子能量沉积与DNA双链断裂空间分布的相关性。为100MeV质子回旋加速器应用于治癌提供技术支撑，为质子治癌有效性和最优化提供基础数据和科学依据。

质子治疗具有对肿瘤细胞杀伤大、对正常组织伤害小的优点，已成为当前我国重点发展的物理疗法之一。在治疗计划中，通常认为质子的相对生物学效应（RBE）值与光子近似并固定为1.1。但最近有数据显示，二者的生物学响应可能存在差异。因此，为了推动我国具有自主知识产权的质子治疗技术的建立，必须开展质子治疗关键物理技术和生物学问题研究。本研究中，依托中国原子能科学研究院自建的100MeV质子回旋加速器和HI-13串列加速器，开展了中能质子扩束、品质诊断、剂量测量及其准确性评估以及低能质子射程调节等关键物理技术研究；以细胞RBE值作为验证体系，对技术手段的可靠性进行了评估；使用不同LET的质子和γ射线，研究了细胞辐射敏感性和DNA 损伤响应与LET 的相关性，探讨了质子能量沉积与DNA 双链断裂损伤的响应机制。结果表明，建立的中能质子扩束技术可产生5cm×5cm范围内均匀性好于90%的照射野；建立的束流测量系统的剂量准确性为90%；研制的低能质子射程移位器可实现最小步长为5μm的Bragg位置可调；细胞验证得到的100MeV质子坪区（LET=0.8keV/μm）的RBE值为1.1左右，与国际上相一致；细胞辐射敏感性依赖于质子LET，具有较高LET的3.6keV/μm的质子在37%和10%存活水平，RBE值分别为1.5和1.52；DNA双链断裂损伤具有LET依赖性，主要表现为γ-H2AX焦点数量和大小的变化，其中焦点数量与LET正相关，焦点大小以较高 LET尺寸大且持续时间更长，揭示了随着质子LET值增加，粒子能量沉积在细胞中增多，辐射诱发的集簇性损伤增加，这与高LET辐射诱发的集簇性损伤的双链断裂聚集的结论相一致。此项工作提升了国内中能质子辐射效应研究的能力，有助于今后我国填补在中能质子辐射生物学效应研究领域实验数据的空白。获得的研究结果为阐明质子治癌相关生物物理机制提供了基础数据，为质子治疗有效性评价提供了科学依据。