Schneider Uwe, Vasi Fabiano, Besserer Jürgen
Department of Physics, Science Faculty, University of Zürich, Zürich, Switzerland.
Radiotherapy Hirslanden, Witellikerstrasse 40, CH-8032, Zürich, Switzerland.
PLoS One. 2016 Oct 19;11(10):e0164929. doi: 10.1371/journal.pone.0164929. eCollection 2016.
When fractionation schemes for hypofractionation and stereotactic body radiotherapy are considered, a reliable cell survival model at high dose is needed for calculating doses of similar biological effectiveness. An alternative to the LQ-model is the track-event theory which is based on the probabilities for one- and two two-track events. A one-track-event (OTE) is always represented by at least two simultaneous double strand breaks. A two-track-event (TTE) results in one double strand break. Therefore at least two two-track-events on the same or different chromosomes are necessary to produce an event which leads to cell sterilization. It is obvious that the probabilities of OTEs and TTEs must somehow depend on the geometrical structure of the chromatin. In terms of the track-event theory the ratio ε of the probabilities of OTEs and TTEs includes the geometrical dependence and is obtained in this work by simple Monte Carlo simulations.
For this work it was assumed that the anchors of loop forming chromatin are most sensitive to radiation induced cell deaths. Therefore two adjacent tetranucleosomes representing the loop anchors were digitized. The probability ratio ε of OTEs and TTEs was factorized into a radiation quality dependent part and a geometrical part: ε = εion ∙ εgeo. εgeo was obtained for two situations, by applying Monte Carlo simulation for DNA on the tetranucleosomes itself and for linker DNA. Low energy electrons were represented by randomly distributed ionizations and high energy electrons by ionizations which were simulated on rays. εion was determined for electrons by using results from nanodosimetric measurements. The calculated ε was compared to the ε obtained from fits of the track event model to 42 sets of experimental human cell survival data.
When the two tetranucleosomes are in direct contact and the hits are randomly distributed εgeo and ε are 0.12 and 0.85, respectively. When the hits are simulated on rays εgeo and ε are 0.10 and 0.71. For the linker-DNA εgeo and ε for randomly distributed hits are 0.010 and 0.073, and for hits on rays 0.0058 and 0.041, respectively. The calculated ε fits the experimentally obtained ε = 0.64±0.32 best for hits on the tetranucleosome when they are close to each other both, for high and low energy electrons.
The parameter εgeo of the track event model was obtained by pure geometrical considerations of the chromatin structure and is 0.095 ± 0.022. It can be used as a fixed parameter in the track-event theory.
在考虑大分割放疗和立体定向体部放疗的分割方案时，需要一个可靠的高剂量细胞存活模型来计算具有相似生物学效应的剂量。线性二次模型（LQ模型）的一种替代方法是径迹-事件理论，该理论基于单径迹事件和双径迹事件的概率。单径迹事件（OTE）总是由至少两个同时发生的双链断裂表示。双径迹事件（TTE）导致一个双链断裂。因此，在同一或不同染色体上至少需要两个双径迹事件才能产生导致细胞失活的事件。很明显，OTE和TTE的概率必须在某种程度上取决于染色质的几何结构。根据径迹-事件理论，OTE和TTE概率的比值ε包含几何依赖性，并且在本研究中通过简单的蒙特卡罗模拟获得。
在本研究中，假设形成环的染色质的锚对辐射诱导的细胞死亡最敏感。因此，对代表环锚的两个相邻四核小体进行了数字化处理。OTE和TTE的概率比ε被分解为与辐射品质相关的部分和几何部分：ε = ε离子 ∙ ε几何。通过对四核小体自身上的DNA以及连接DNA应用蒙特卡罗模拟，在两种情况下获得了ε几何。低能电子由随机分布的电离表示，高能电子由在射线上模拟的电离表示。通过使用纳米剂量测量的结果确定电子的ε离子。将计算得到的ε与通过将径迹事件模型拟合到42组实验人类细胞存活数据而获得的ε进行比较。
当两个四核小体直接接触且命中随机分布时，ε几何和ε分别为0.12和0.85。当在射线上模拟命中时，ε几何和ε分别为0.10和0.71。对于连接DNA，随机分布命中时的ε几何和ε分别为0.010和0.073，在射线上命中时分别为0.0058和0.041。对于高、低能电子，当四核小体彼此靠近时，计算得到的ε最适合实验获得的ε = 0.64±0.32。
径迹事件模型的参数ε几何是通过对染色质结构的纯几何考虑获得的，为0.095±0.022。它可以用作径迹-事件理论中的一个固定参数。
