Clinic and Polyclinic for Radiation Therapy, Medical School, University of Duisburg-Essen, 45122 Essen, Germany.
Institute of Medical Radiation Biology, Medical School, University of Duisburg-Essen, 45122 Essen, Germany.
Molecules. 2022 Feb 24;27(5):1540. doi: 10.3390/molecules27051540.
Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.
利用低和高线性能量转移（低-/高-LET）电离辐射（IR）的带电粒子放疗（CPRT）是一种有前途的癌症治疗方式，具有独特的物理能量沉积特性。CPRT 能够将所需的剂量集中输送到肿瘤部位，从而实现更好的肿瘤控制和减少正常组织毒性。它提高了患者的整体辐射耐受性和生存机会。通过更好地了解 IR 控制生物学效应的机制及其对 LET 的依赖性，可以进一步改进 CPRT。越来越多的证据表明，高 LET IR 诱导更复杂甚至簇状 DNA 双链断裂（DSB），这对细胞内稳态极其重要，对基因组完整性构成了相当大的威胁。然而，从癌症管理的角度来看，相同的 DSB 特征支持预期的治疗益处，是指导当前增加重离子（HI）在放疗中应用的基本原理的核心。在这里，我们综述了高 LET IR 引起的特定细胞 DNA 损伤反应（DDR），并将其与低 LET IR 引起的 DDR 进行了比较。我们强调了诱导的 DSB 形式及其对 DDR 的影响的差异。此外，我们分析了不同初始形式的 DSB 如何通过激活 DNA 末端切除来调节 DSB 修复途径之间的相互作用。我们假设，在复杂的 DSB 和 DSB 簇中，增加的 DNA 末端切除通过增加与切除相关的修复途径的参与来协调。此外，我们总结了证据表明，在暴露于高 LET IR 后，易错过程通过仍有待阐明的机制，胜过高保真同源重组（HR）。最后，我们综述了特定 DDR 相关翻译后修饰和癌细胞凋亡的高 LET 依赖性。我们相信，深入研究高 LET IR 特有的生物学效应将有助于建立用于未来个体化治疗策略的预测和预后标志物，并增强开发在太空旅行中改善辐射防护的有效对策的前景。
