Bodgi Larry, Foray Nicolas
a Institut National de la Santé et de la Recherche Médicale, UMR 1052, Radiobiology Group, Cancer Research Centre of Lyon , Lyon , France ;
b St-Joseph University , Faculty of Sciences , Beirut , Lebanon.
Int J Radiat Biol. 2016;92(3):117-31. doi: 10.3109/09553002.2016.1135260.
For 50 years, cellular radiosensitivity has been defined in vitro as the lack of clonogenic capacity of irradiated cells and its mathematical link with dose has been described by the target theory. Among the numerous formulas provided from the target theory, the linear-quadratic (LQ) model empirically describes cell survival as a negative exponential of a second degree polynomial dose-function in which αD is the linear component and βD(2) is the quadratic one. The LQ model is extensively used in radiobiology (to describe survival curves) and in radiotherapy (the α/β ratio indicates whether tissue reactions can occur early or late after the treatment). However, no biological interpretation of the LQ parameters was proposed to explain together the radiation response in a wide dose range, the radiosensitivity of some genetic syndromes caused by the mutation of cytoplasmic proteins and the hyper-radiosensitivity phenomenon specific to low-dose.
From a solid amount of experimental data, we hypothesized that the major forms of ataxia telangiectasia mutated (ATM) are cytoplasmic dimers and that ionizing radiation induce ATM monomerization. The resulting ATM monomers diffuse into nucleus to facilitate double-strand-breaks (DSB) recognition and repair. Such hypotheses lead to a coherent molecular interpretation of the LQ model by considering the yield of recognized but unrepaired (α-type) DSB and the non-recognized (β-type) DSB. The notion of cell tolerance to unrepaired DSB was introduced by considering that not all DSB are lethal. Cell survival and DSB repair and signaling immunofluorescence data from 42 normal skin fibroblast and 18 tumor human cell lines were used to verify the validity of this biomathematical model proposed.
Our model is validated at different levels by one of the widest spectrum of radiosensitivity. That mathematical developments of the present model imply that β is a Lorentzian function of α was confirmed experimentally. Our model is also relevant to describe the hypersensitivity to low-dose phenomenon.
Our model provides a very general picture of human radiosensitivity, independently of the dose, the cell type and the genetic status.
五十年来，细胞放射敏感性在体外被定义为受照射细胞缺乏克隆形成能力，并且其与剂量的数学关系已由靶理论进行描述。在靶理论提供的众多公式中，线性二次（LQ）模型根据经验将细胞存活描述为二次多项式剂量函数的负指数，其中αD为线性成分，βD²为二次成分。LQ模型广泛应用于放射生物学（用于描述存活曲线）和放射治疗（α/β比值表明组织反应是在治疗后早期还是晚期发生）。然而，尚未有人提出对LQ参数的生物学解释，以共同说明在宽剂量范围内的辐射反应、由细胞质蛋白突变引起的某些遗传综合征的放射敏感性以及低剂量特有的超放射敏感性现象。
基于大量实验数据，我们假设共济失调毛细血管扩张症突变基因（ATM）的主要形式是细胞质二聚体，并且电离辐射会诱导ATM单体化。产生的ATM单体扩散到细胞核中以促进双链断裂（DSB）的识别和修复。通过考虑已识别但未修复的（α型）DSB和未识别的（β型）DSB的产生，这些假设得出了对LQ模型的连贯分子解释。通过考虑并非所有DSB都是致命的，引入了细胞对未修复DSB的耐受性概念。使用来自42个正常皮肤成纤维细胞系和18个人类肿瘤细胞系的细胞存活、DSB修复和信号免疫荧光数据来验证所提出的这种生物数学模型的有效性。
我们的模型在最广泛的放射敏感性范围内的不同水平上得到了验证。本模型的数学推导表明β是α的洛伦兹函数，这一点得到了实验证实。我们的模型也适用于描述对低剂量现象的超敏感性。
我们的模型提供了一幅非常普遍的人类放射敏感性图景，与剂量、细胞类型和遗传状态无关。
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