Keam Synat, MacKinnon Kelly M, D'Alonzo Rebecca A, Gill Suki, Ebert Martin A, Nowak Anna K, Cook Alistair M
National Centre for Asbestos Related Diseases, Institute for Respiratory Health, Perth, Australia.
Medical School, Mathematics and Computing, University of Western Australia, Perth, Australia.
Adv Radiat Oncol. 2022 Jul 21;7(6):101013. doi: 10.1016/j.adro.2022.101013. eCollection 2022 Nov-Dec.
To characterize the cellular responses of murine and human mesothelioma cell lines to different doses of photon radiation with a long-term aim of optimizing a clinically relevant in vivo model in which to study the interaction of radiation therapy and immunotherapy combinations.
Two murine mesothelioma cell lines (AB1 and AE17) and 3 human cell lines (BYE, MC, and JU) were used in the study. Cells were treated with increasing doses of photon radiation. DNA damage, DNA repair, cell proliferation, and apoptosis at different time points after irradiation were quantified by flow cytometry, and cell survival probability was examined using clonogenic survival assay.
DNA damage increased with escalating dose in all cell lines. Evident G2/M arrest and reduced cell proliferation were observed after irradiation with 8 Gy. DNA repair was uniformly less efficient at higher compared with lower radiation-fraction doses. The apoptosis dose response varied between cell lines, with greater apoptosis observed at 16 Gy with human BYE and murine AB1 cell lines but less for other studied cell lines, regardless of dose and time. The α/β ratio from the cell survival fraction of human mesothelioma cell lines was smaller than from murine ones, suggesting human cell lines in our study were more sensitive to a change of dose per fraction than were murine mesothelioma cell lines. However, in all studied cell lines, colony formation was completely inhibited at 8 Gy.
A threshold dose of 8 Gy appeared to be appropriate for hypofractionated radiation therapy. However, the radiation therapy doses between 4 and 8 Gy remain to be systematically analyzed. These observations provide an accurate picture of the in vitro response of mesothelioma cell lines to photon irradiation and characterize the heterogeneity between human and murine cell lines. This information may guide in vivo experiments and the strengths and limitations of extrapolation from murine experimentation to potential human translation.
表征小鼠和人源间皮瘤细胞系对不同剂量光子辐射的细胞反应，长期目标是优化一个临床相关的体内模型，用于研究放射治疗与免疫治疗联合的相互作用。
本研究使用了两种小鼠间皮瘤细胞系（AB1和AE17）和三种人源细胞系（BYE、MC和JU）。细胞接受递增剂量的光子辐射。通过流式细胞术对辐照后不同时间点的DNA损伤、DNA修复、细胞增殖和凋亡进行定量，并使用克隆形成存活试验检测细胞存活概率。
所有细胞系中，DNA损伤随剂量增加而增加。照射8 Gy后观察到明显的G2/M期阻滞和细胞增殖减少。与较低的分次辐射剂量相比，较高剂量时DNA修复效率普遍较低。细胞系之间的凋亡剂量反应有所不同，人源BYE细胞系和小鼠AB1细胞系在16 Gy时观察到更大程度的凋亡，但其他研究的细胞系凋亡程度较小，且与剂量和时间无关。人源间皮瘤细胞系的细胞存活分数得出的α/β比值小于小鼠细胞系，表明我们研究中的人源细胞系比分次剂量变化更敏感。然而，在所有研究的细胞系中，8 Gy时集落形成被完全抑制。
8 Gy的阈值剂量似乎适用于大分割放射治疗。然而，4至8 Gy之间的放射治疗剂量仍有待系统分析。这些观察结果准确描绘了间皮瘤细胞系对光子辐照的体外反应，并表征了人源和小鼠细胞系之间的异质性。这些信息可能指导体内实验以及从小鼠实验外推至潜在人体转化的优势和局限性。
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