Gago-Arias Araceli, Aguiar Pablo, Espinoza Ignacio, Sánchez-Nieto Beatriz, Pardo-Montero Juan
Instituto de Física, Pontificia Universidad Católica de Chile, Santiago, Chile.
Phys Med Biol. 2016 Feb 7;61(3):1204-16. doi: 10.1088/0031-9155/61/3/1204. Epub 2016 Jan 20.
The resistance of hypoxic cells to radiation, due to the oxygen dependence of radiosensitivity, is well known and must be taken into account to accurately calculate the radiation induced cell death. A proper modelling of the response of tumours to radiation requires deriving the distribution of oxygen at a microscopic scale. This usually involves solving the reaction-diffusion equation in tumour voxels using a vascularization distribution model. Moreover, re-oxygenation arises during the course of radiotherapy, one reason being the increase of available oxygen caused by cell killing, which can turn hypoxic tumours into oxic. In this work we study the effect of cell death kinetics in tumour oxygenation modelling, analysing how it affects the timing of re-oxygenation, surviving fraction and tumour control. Two models of cell death are compared, an instantaneous cell killing, mimicking early apoptosis, and a delayed cell death scenario in which cells can die shortly after being damaged, as well as long after irradiation. For each of these scenarios, the decrease in oxygen consumption due to cell death can be computed globally (macroscopic voxel average) or locally (microscopic). A re-oxygenation model already used in the literature, the so called full re-oxygenation, is also considered. The impact of cell death kinetics and re-oxygenation on tumour responses is illustrated for two radiotherapy fractionation schemes: a conventional schedule, and a hypofractionated treatment. The results show large differences in the doses needed to achieve 50% tumour control for the investigated cell death models. Moreover, the models affect the tumour responses differently depending on the treatment schedule. This corroborates the complex nature of re-oxygenation, showing the need to take into account the kinetics of cell death in radiation response models.
由于放射敏感性对氧的依赖性，缺氧细胞对辐射具有抗性，这是众所周知的，在准确计算辐射诱导的细胞死亡时必须予以考虑。要对肿瘤对辐射的反应进行恰当建模，需要在微观尺度上推导氧的分布。这通常涉及使用血管化分布模型求解肿瘤体素中的反应扩散方程。此外，在放射治疗过程中会发生再氧合，一个原因是细胞杀伤导致可用氧增加，这可使缺氧肿瘤变为富氧肿瘤。在这项工作中，我们研究细胞死亡动力学在肿瘤氧合建模中的作用，分析其如何影响再氧合时间、存活分数和肿瘤控制。比较了两种细胞死亡模型，一种是模拟早期凋亡的瞬时细胞杀伤模型，另一种是细胞在受损后不久以及照射后很长时间都可能死亡的延迟细胞死亡模型。对于每种情况，可从全局（宏观体素平均值）或局部（微观）计算由于细胞死亡导致的氧消耗减少。还考虑了文献中已使用的一种再氧合模型，即所谓的完全再氧合模型。针对两种放射治疗分割方案说明了细胞死亡动力学和再氧合对肿瘤反应的影响：一种是常规方案，另一种是大分割治疗。结果表明，对于所研究的细胞死亡模型，实现50%肿瘤控制所需的剂量存在很大差异。此外，这些模型根据治疗方案对肿瘤反应的影响也不同。这证实了再氧合的复杂性，表明在辐射反应模型中需要考虑细胞死亡动力学。
