Iliakis George, Wu Wenqi, Wang Minli
University of Duisburg-Essen Medical School, Institute of Medical Radiation Biology, Essen, Germany.
Int J Hyperthermia. 2008 Feb;24(1):17-29. doi: 10.1080/02656730701784782.
Heat shock is one of the most effective radiosensitizers known. As a result, combination of heat with ionizing radiation (IR) is considered a promising strategy in the management of human cancer. The mechanism of heat radiosensitization has been the subject of extensive work but a unifying mechanistic model is presently lacking. To understand the cause of excessive death in irradiated cells after heat exposure, it is necessary to characterize the lesion(s) underlying the effect and to determine which of the pathways processing this lesion are affected by heat. Since DNA double strand breaks (DSBs) are the main cause for IR-induced cell death, inhibition of DSB processing has long been considered a major candidate for heat radiosensitization. However, effective radiosensitization of mutants with defects in homologous recombination repair (HRR), or in DNA-PK dependent non-homologous end joining (D-NHEJ), the two primary pathways of DSB repair, has led to the formulation of models excluding DSBs as a cause for this phenomenon and attributing heat radiosensitization to inhibition of base damage processing. Since direct evidence for a major role of base damage in heat radiosensitization, or in IR-induced killing for that matter, is scarce and new insights in DSB repair allow alternative interpretations of existing data with repair mutants, we attempt here a re-evaluation of the role of DSBs and their repair in heat radiosensitization. First, we reanalyse data obtained with various DSB repair mutants on first principles and in the light of the recent recognition that alternative pathways of NHEJ, operating as backup (B-NHEJ), substantially contribute to DSB repair and thus probably also to heat radiosensitization. Second, we review aspects of combined action of heat and radiation, such as modulation in the cell-cycle-dependent variation in radiosensitivity to killing, as well as heat radiosensitization as a function of LET, and examine whether the observed effects are compatible with DSB repair inhibition. We conclude with a model reclaiming a central role for DSBs in heat radiosensitization.
热休克是已知最有效的放射增敏剂之一。因此，热与电离辐射（IR）联合应用被认为是人类癌症治疗中一种有前景的策略。热放射增敏的机制一直是大量研究的主题，但目前缺乏一个统一的机制模型。为了理解热暴露后受辐照细胞过度死亡的原因，有必要表征这种效应背后的损伤，并确定处理这种损伤的哪些途径受到热的影响。由于DNA双链断裂（DSB）是IR诱导细胞死亡的主要原因，长期以来，抑制DSB处理一直被认为是热放射增敏的主要候选机制。然而，对同源重组修复（HRR）或DNA-PK依赖的非同源末端连接（D-NHEJ）这两种DSB修复的主要途径存在缺陷的突变体进行有效放射增敏，导致了一些模型的形成，这些模型排除了DSB是这种现象的原因，并将热放射增敏归因于碱基损伤处理的抑制。由于碱基损伤在热放射增敏或IR诱导杀伤中起主要作用的直接证据很少，并且DSB修复的新见解允许对现有修复突变体数据进行替代解释，我们在此尝试重新评估DSB及其修复在热放射增敏中的作用。首先，我们根据第一原理重新分析用各种DSB修复突变体获得的数据，并鉴于最近认识到作为备用途径（B-NHEJ）运作的NHEJ替代途径对DSB修复有很大贡献，因此可能也对热放射增敏有很大贡献。其次，我们回顾热与辐射联合作用的各个方面，如细胞周期依赖性放射敏感性变化对杀伤的调节，以及热放射增敏作为传能线密度（LET）的函数，并检查观察到的效应是否与DSB修复抑制相容。我们以一个恢复DSB在热放射增敏中核心作用的模型作为结论。
