Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114.
Department of Engineering Physics, Tsinghua University, Beijing 100084, P.R. China.
Radiat Res. 2020 Jul 8;194(1):9-21. doi: 10.1667/RR15531.1.
The cellular response to ionizing radiation continues to be of significant research interest in cancer radiotherapy, and DNA is recognized as the critical target for most of the biologic effects of radiation. Incident particles can cause initial DNA damages through physical and chemical interactions within a short time scale. Initial DNA damages can undergo repair via different pathways available at different stages of the cell cycle. The misrepair of DNA damage results in genomic rearrangement and causes mutations and chromosome aberrations, which are drivers of cell death. This work presents an integrated study of simulating cell response after proton irradiation with energies of 0.5-500 MeV (LET of 60-0.2 keV/µm). A model of a whole nucleus with fractal DNA geometry was implemented in TOPAS-nBio for initial DNA damage simulations. The default physics and chemistry models in TOPAS-nBio were used to describe interactions of primary particles, secondary particles, and radiolysis products within the nucleus. The initial DNA double-strand break (DSB) yield was found to increase from 6.5 DSB/Gy/Gbp at low-linear energy transfer (LET) of 0.2 keV/µm to 21.2 DSB/Gy/Gbp at high LET of 60 keV/µm. A mechanistic repair model was applied to predict the characteristics of DNA damage repair and dose response of chromosome aberrations. It was found that more than 95% of the DSBs are repaired within the first 24 h and the misrepaired DSB fraction increases rapidly with LET and reaches 15.8% at 60 keV/µm with an estimated chromosome aberration detection threshold of 3 Mbp. The dicentric and acentric fragment yields and the dose response of micronuclei formation after proton irradiation were calculated and compared with experimental results.
细胞对电离辐射的反应仍然是癌症放射治疗中重要的研究热点，而 DNA 被认为是辐射的大多数生物学效应的关键靶标。入射粒子可以在短时间内通过物理和化学相互作用导致初始 DNA 损伤。初始 DNA 损伤可以通过细胞周期不同阶段提供的不同途径进行修复。DNA 损伤的错误修复会导致基因组重排，从而导致突变和染色体畸变，这是细胞死亡的驱动因素。这项工作综合研究了用能量为 0.5-500 MeV（LET 为 60-0.2 keV/μm）的质子辐照后细胞的反应。在 TOPAS-nBio 中实现了具有分形 DNA 几何形状的整个核模型，用于初始 DNA 损伤模拟。TOPAS-nBio 中的默认物理和化学模型用于描述核内初级粒子、次级粒子和辐射分解产物的相互作用。发现初始 DNA 双链断裂（DSB）产额从低线性能量转移（LET）为 0.2 keV/μm 时的 6.5 DSB/Gy/Gbp 增加到 LET 为 60 keV/μm 时的 21.2 DSB/Gy/Gbp。应用一种机制修复模型来预测 DNA 损伤修复和染色体畸变剂量反应的特征。结果发现，超过 95%的 DSB 在 24 小时内修复，错误修复的 DSB 分数随 LET 迅速增加，在 60 keV/μm 时达到 15.8%，估计染色体畸变检测阈值为 3 Mbp。计算并比较了质子辐照后着丝粒和无着丝粒片段产额以及微核形成的剂量反应。
