Biological Consequences of Radiation-induced DNA Damage: Relevance to Radiotherapy
Biological Consequences of Radiation-induced DNA Damage: Relevance to Radiotherapy
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DOI：
10.1016/j.clon.2013.06.007
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发表时间：
2013-10-01
影响因子：
3.4
通讯作者：
O'Neill, P.
中科院分区：
文献类型：
--
作者：
Lomax, M. E.;Folkes, L. K.;O'Neill, P.
暴露的肿瘤组织的DNA损伤导致细胞死亡是电离辐射的有害作用之一，其被用于放射治疗，具有有益的后果。在辐射的电离轨道通过期间的离散能量沉积的图案定义了DNA中诱导的损伤的空间分布，其中DNA损伤位点的一部分包含损伤簇，形成在几纳米内，相对于内源性诱导的个体损伤的背景。这些聚集的DNA损伤位点，可以被认为是电离辐射的特征，是电离辐射的有害生物后果的基础。开发的概念部分依赖于电离辐射产生显着水平的聚集DNA损伤，包括复杂的双链断裂（DSB），以杀死肿瘤细胞，因为聚集损伤部位难以修复。这种使用特定修复途径的成簇DNA损伤的修复性降低可用于治疗癌症的放射疗法。我们讨论了一些潜在的策略，以提高辐射敏感性，通过靶向辐射诱导的簇状损伤和复杂的DNA DSB的修复途径，通过抑制特定的蛋白质，不需要在内源性损伤的修复途径。电离辐射造成的DNA损伤的种类和严重程度也受到肿瘤微环境的影响，对细胞的氧状态特别敏感。例如，已知一氧化氮会影响缺氧条件下辐射诱导的损伤类型。一种潜在的战略的基础上生物还原激活的前体药物释放一氧化氮作为一种方法来提供一氧化氮在放射治疗过程中缺氧肿瘤进行了讨论。这篇综述的最终目的是激发人们对辐射诱导的DNA损伤的复杂性的认识如何有助于放射治疗的发展的思考。(C)2013年皇家放射科医师学院。由爱思唯尔有限公司出版。保留所有权利。
DNA damage of exposed tumour tissue leading to cell death is one of the detrimental effects of ionising radiation that is exploited, with beneficial consequences, for radiotherapy. The pattern of the discrete energy depositions during passage of the ionising track of radiation defines the spatial distribution of lesions induced in DNA with a fraction of the DNA damage sites containing clusters of lesions, formed over a few nanometres, against a background of endogenously induced individual lesions. These clustered DNA damage sites, which may be considered as a signature of ionising radiation, underlie the deleterious biological consequences of ionising radiation. The concepts developed rely in part on the fact that ionising radiation creates significant levels of clustered DNA damage, including complex double-strand breaks (DSB), to kill tumour cells as clustered damage sites are difficult to repair. This reduced repairability of clustered DNA damage using specific repair pathways is exploitable in radiotherapy for the treatment of cancer. We discuss some potential strategies to enhance radiosensitivity by targeting the repair pathways of radiation-induced clustered damage and complex DNA DSB, through inhibition of specific proteins that are not required in the repair pathways for endogenous damage. The variety and severity of DNA damage from ionising radiation is also influenced by the tumour microenvironment, being especially sensitive to the oxygen status of the cells. For instance, nitric oxide is known to influence the types of damage induced by radiation under hypoxic conditions. A potential strategy based on bioreductive activation of pro-drugs to release nitric oxide is discussed as an approach to deliver nitric oxide to hypoxic tumours during radiotherapy. The ultimate aim of this review is to stimulate thinking on how knowledge of the complexity of radiation-induced DNA damage may contribute to the development of adjuncts to radiotherapy. (C) 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.