Taleei Reza
Division of Medical Physics, Department of Radiation Oncology, University of Virginia, Charlottesville, VA.
Radiat Prot Dosimetry. 2019 May 1;183(1-2):75-78. doi: 10.1093/rpd/ncy304.
Proton and carbon therapy are the main choices of particle therapy for cancer treatment. Particle dose distribution is superior to conventional photon therapy dose distribution due to Bragg peak. However, the basic biology of cellular damage and cell death is not well understood. The aim of this work is to present a mechanistic model of double strand break (DSB) repair that predicts the repair kinetics of damage induced by particles employed in cancer therapy. Monte Carlo Track Damage Simulation (MCDS) was employed to model DNA damage. The frequency of DSB and SSB was computed for proton and carbon ions. DSBs were subjected to repair model to calculate the repair kinetics. Two distinct DSB repair models dependent on the cell cycle were proposed. The DSB repair model contains non-homologous end joining (NHEJ), homologous recombination (HR) and back up non-homologous end joining (B-NHEJ) repair processes. The DSB complexity results in the switch in the repair pathway from NHEJ to a slower process that starts with DSB end resection. DSB end resection in early S and G1 phases of the cell cycle enhances the B-NHEJ repair pathway, while in late S and G2 phases of the cell cycle promotes HR repair pathway. The repair model was transformed to a set of nonlinear differential equations. The model calculates the overall repair kinetics and protein temporal repair activity at the site of damage. The damage and repair model provides a detailed mechanistic understanding of all processes that are involved in the damage induction and repair. The number of DSB and their complexity increase as the particle energy decreases due to the proximity of particle interactions in water. The repair kinetics show a biphasic behaviour that is due to the NHEJ fast repair of simple type DSB and HR slow repair of complex type DSB.
质子和碳离子疗法是癌症治疗中粒子疗法的主要选择。由于布拉格峰，粒子剂量分布优于传统光子疗法的剂量分布。然而，细胞损伤和细胞死亡的基本生物学机制尚未得到充分理解。这项工作的目的是提出一种双链断裂（DSB）修复的机制模型，该模型可预测癌症治疗中使用的粒子诱导损伤的修复动力学。采用蒙特卡罗径迹损伤模拟（MCDS）对DNA损伤进行建模。计算了质子和碳离子的DSB和SSB频率。将DSB应用于修复模型以计算修复动力学。提出了两种依赖于细胞周期的不同DSB修复模型。DSB修复模型包含非同源末端连接（NHEJ）、同源重组（HR）和备用非同源末端连接（B-NHEJ）修复过程。DSB的复杂性导致修复途径从NHEJ切换到以DSB末端切除开始的较慢过程。细胞周期早期S期和G1期的DSB末端切除增强了B-NHEJ修复途径，而细胞周期晚期S期和G2期则促进HR修复途径。将修复模型转化为一组非线性微分方程。该模型计算损伤部位的整体修复动力学和蛋白质的瞬时修复活性。损伤和修复模型提供了对损伤诱导和修复所涉及的所有过程的详细机制理解。由于水中粒子相互作用的接近性，随着粒子能量降低，DSB的数量及其复杂性增加。修复动力学表现出双相行为，这是由于简单类型DSB的NHEJ快速修复和复杂类型DSB的HR缓慢修复所致。
