PDF(Pubmed)
Abstract：
The use of charged particle radiotherapy is currently increasing, but combination therapy with DNA repair inhibitors remains to be exploited in the clinic. The high-linear energy transfer (LET) radiation delivered by charged particles causes clustered DNA damage, which is particularly effective in destroying cancer cells. Whether the DNA damage response to this type of damage is different from that elicited in response to low-LET radiation, and if and how it can be targeted to increase treatment efficacy, is not fully understood. Although several preclinical studies have reported radiosensitizing effects when proton or carbon ion irradiation is combined with inhibitors of, e.g., PARP, ATR, ATM, or DNA-PKcs, further exploration is required to determine the most effective treatments. Here, we examine what is known about repair pathway choice in response to high- versus low-LET irradiation, and we discuss the effects of inhibitors of these pathways when combined with protons and carbon ions. Additionally, we explore the potential effects of DNA repair inhibitors on antitumor immune signaling upon proton and carbon ion irradiation. Due to the reduced effect on healthy tissue and better immune preservation, particle therapy may be particularly well suited for combination with DNA repair inhibitors.
摘要：
目前带电粒子放射治疗的使用越来越多,但是与DNA修复抑制剂的联合治疗仍有待临床开发。带电粒子传递的高线性能量转移（LET）辐射会导致成簇的DNA损伤，这对破坏癌细胞特别有效。对这种类型损伤的DNA损伤反应是否不同于对低LET辐射的反应，以及它是否以及如何能够有针对性地提高治疗效果，没有完全理解。尽管一些临床前研究报道了质子或碳离子照射与抑制剂联合使用时的放射增敏作用，例如，PARP,ATR,ATM,或DNA-PKcs，需要进一步探索以确定最有效的治疗方法。这里,我们研究了对高与低LET照射的修复途径选择的已知情况，我们讨论了这些途径的抑制剂与质子和碳离子结合时的作用。此外,我们探讨了DNA修复抑制剂对质子和碳离子照射抗肿瘤免疫信号的潜在影响。由于对健康组织的影响降低和更好的免疫保存，粒子疗法可能特别适合与DNA修复抑制剂组合。
