Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Manchester, UK.
Sci Rep. 2018 Feb 8;8(1):2654. doi: 10.1038/s41598-018-21111-8.
This work uses Monte Carlo simulations to investigate the dependence of residual and misrepaired double strand breaks (DSBs) at 24 hours on the initial damage pattern created during ion therapy. We present results from a nanometric DNA damage simulation coupled to a mechanistic model of Non-Homologous End Joining, capable of predicting the position, complexity, and repair of DSBs. The initial damage pattern is scored by calculating the average number of DSBs within 70 nm from every DSB. We show that this local DSB density, referred to as the cluster density, can linearly predict misrepair regardless of ion species. The models predict that the fraction of residual DSBs is constant, with 7.3% of DSBs left unrepaired following 24 hours of repair. Through simulation over a range of doses and linear energy transfer (LET) we derive simple correlations capable of predicting residual and misrepaired DSBs. These equations are applicable to ion therapy treatment planning where both dose and LET are scored. This is demonstrated by applying the correlations to an example of a clinical proton spread out Bragg peak. Here we see a considerable biological effect past the distal edge, dominated by residual DSBs.
这项工作使用蒙特卡罗模拟来研究在离子治疗过程中形成的初始损伤模式对 24 小时时残留和修复错误的双链断裂 (DSB) 的依赖性。我们展示了一种纳米级 DNA 损伤模拟与非同源末端连接的机制模型相结合的结果，该模型能够预测 DSB 的位置、复杂性和修复。通过计算每个 DSB 周围 70nm 内的 DSB 平均数量来评估初始损伤模式。我们表明，这种局部 DSB 密度，称为簇密度，可以线性预测错误修复，而与离子种类无关。该模型预测残留 DSB 的分数是恒定的，在 24 小时的修复后，有 7.3%的 DSB 未被修复。通过在一系列剂量和线性能量转移 (LET) 下进行模拟，我们得出了能够预测残留和修复错误的 DSB 的简单相关性。这些方程适用于同时记录剂量和 LET 的离子治疗计划。通过将相关性应用于临床质子扩展布拉格峰的一个例子来证明这一点。在这里，我们看到在远侧边缘之外存在相当大的生物学效应，主要是由残留的 DSB 引起的。
