Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
Biosci Rep. 2023 Oct 31;43(10). doi: 10.1042/BSR20222586.
Radiotherapy is utilised in the treatment of ∼50% of all human cancers, which predominantly employs photon radiation. However, particle radiotherapy elicits significant benefits over conventional photons due to more precise dose deposition and increased linear energy transfer (LET) that generates an enhanced therapeutic response. Specifically, proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) are characterised by a Bragg peak, which generates a low entrance radiation dose, with the majority of the energy deposition being defined within a small region which can be specifically targeted to the tumour, followed by a low exit dose. PBT is deemed relatively low-LET whereas CIRT is more densely ionising and therefore high LET. Despite the radiotherapy type, tumour cell killing relies heavily on the introduction of DNA damage that overwhelms the repair capacity of the tumour cells. It is known that DNA damage complexity increases with LET that leads to enhanced biological effectiveness, although the specific DNA repair pathways that are activated following the different radiation sources is unclear. This knowledge is required to determine whether specific proteins and enzymes within these pathways can be targeted to further increase the efficacy of the radiation. In this review, we provide an overview of the different radiation modalities and the DNA repair pathways that are responsive to these. We also provide up-to-date knowledge of studies examining the impact of LET and DNA damage complexity on DNA repair pathway choice, followed by evidence on how enzymes within these pathways could potentially be therapeutically exploited to further increase tumour radiosensitivity, and therefore radiotherapy efficacy.
放射疗法被用于治疗约 50%的人类癌症，主要采用光子辐射。然而，由于更精确的剂量沉积和增加的线性能量转移（LET），粒子放射疗法产生了显著的益处，从而产生了增强的治疗反应。具体而言，质子束疗法（PBT）和碳离子放射疗法（CIRT）的特点是布拉格峰，其产生低入口辐射剂量，大部分能量沉积在可以专门针对肿瘤的小区域内，然后是低出口剂量。PBT 被认为是相对低 LET 的，而 CIRT 则更密集电离，因此是高 LET。尽管放射治疗类型不同，但肿瘤细胞杀伤主要依赖于引入的 DNA 损伤，这种损伤超过了肿瘤细胞的修复能力。已知 DNA 损伤复杂性随 LET 增加而增加，从而提高了生物学效应，尽管尚不清楚不同辐射源引发的具体 DNA 修复途径。这一知识对于确定这些途径中的特定蛋白质和酶是否可以被靶向以进一步提高辐射的疗效是必要的。在这篇综述中，我们提供了不同放射治疗模式和对这些模式有反应的 DNA 修复途径的概述。我们还提供了关于研究 LET 和 DNA 损伤复杂性对 DNA 修复途径选择影响的最新知识，以及这些途径中的酶如何可能被治疗性地利用以进一步增加肿瘤对放射的敏感性，从而提高放射治疗的疗效。
