Amsterdam UMC location VUmc, Department of Radiation Oncology, Cancer Center Amsterdam, The Netherlands.
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Radiother Oncol. 2020 Jul;148:107-114. doi: 10.1016/j.radonc.2020.04.014. Epub 2020 Apr 17.
Effective combination treatments with fractionated radiotherapy rely on a proper understanding of the dynamic responses that occur during treatment. We explored the effect of clinical fractionated radiotherapy on the development and timing of radioresistance in tumor cells.
Different colon (HT29/HCT116/COLO320/SW480/RKO) and high-grade astrocytoma (D384/U-251MG) cancer cell lines were treated for 6 weeks with daily fractions of 2 Gy, 5 days per week. Clonogenic survival was determined throughout the treatment period. In addition, the radiosensitivity of irradiated and non-irradiated was compared. Finally, the effect of different dose fractions on the development of radioresistance was determined.
All cell lines developed radioresistance within 2-3 weeks during fractionated radiotherapy. This was characterized by the occurrence of a steady state phase of clonogenic survival. In U-251MG cells this was accompanied by increased cell senescence and stemness. After recovering from six weeks of treatment, the radiosensitivity of fractionally irradiated and non-irradiated cells was similar. Including transient radioresistance, described as (α/β), as a factor in the classic LQ model resulted in a perfect fit with the experimental data observed during fractionated radiotherapy. This was confirmed when different dose fractions were applied.
Fractionated irradiation of cancer cells in vitro following clinical radiation schedules induces a reversible radioresistance response. This adaptive response can be included in the LQ model as a function of the dose fraction and the alpha/beta-ratio of a given cell line. These findings warrant further investigation of the mechanisms and clinical relevance of adaptive radioresistance.
有效的分割放疗联合治疗依赖于对治疗过程中发生的动态反应的正确理解。我们探讨了临床分割放疗对肿瘤细胞产生放射抵抗的发展和时间的影响。
用每天 2 Gy、每周 5 天的分割剂量，对不同的结肠（HT29/HCT116/COLO320/SW480/RKO）和高级别神经胶质瘤（D384/U-251MG）癌细胞系进行 6 周的治疗。在整个治疗期间测定克隆存活。此外，还比较了照射和未照射的放射敏感性。最后，确定不同剂量分割对放射抵抗发展的影响。
所有细胞系在分割放疗的 2-3 周内均产生放射抵抗。这表现为克隆存活的稳态阶段的发生。在 U-251MG 细胞中，这伴随着细胞衰老和干细胞特性的增加。从六周的治疗中恢复后，分次照射和未照射细胞的放射敏感性相似。将暂时放射抵抗（描述为（α/β））作为经典 LQ 模型中的一个因素，导致与分割放疗期间观察到的实验数据非常吻合。当应用不同的剂量分割时，这一点得到了证实。
在临床放射治疗计划下，体外分割照射癌细胞会引起可逆的放射抵抗反应。这种适应性反应可以作为剂量分割的函数，并作为给定细胞系的α/β比值，包含在 LQ 模型中。这些发现值得进一步研究适应性放射抵抗的机制和临床相关性。
