Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Transl Res. 2020 Mar;217:33-46. doi: 10.1016/j.trsl.2019.10.003. Epub 2019 Oct 21.
Tumor treating fields (TTFields) is a noninvasive physical modality of cancer therapy that applies low-intensity, intermediate frequency, and alternating electric fields to a tumor. Interference with mitosis was the first mechanism describing the effects of TTFields on cancer cells; however, TTFields was shown to not only reduce the rejoining of radiation-induced DNA double-strand breaks (DSBs), but to also induce DNA DSBs. The mechanism(s) by which TTFields generates DNA DSBs is related to the generation of replication stress including reduced expression of the DNA replication complex genes MCM6 and MCM10 and the Fanconi's Anemia pathway genes. When markers of DNA replication stress as a result of TTFields exposure were examined, newly replicated DNA length was reduced with TTFields exposure time and there was increased R-loop formation. Furthermore, as cells were exposed to TTFields a conditional vulnerability environment developed which rendered cells more susceptible to DNA damaging agents or agents that interfere with DNA repair or replication fork maintenance. The effect of TTFields exposure with concomitant exposure to cisplatin or PARP inhibition, the combination of TTFields plus concomitant PARP inhibition followed by radiation, or radiation alone at the end of a TTFields exposure were all synergistic. Finally, gene expression analysis of 47 key mitosis regulator genes suggested that TTFields-induced mitotic aberrations and DNA damage/replication stress events, although intimately linked to one another, are likely initiated independently of one another. This suggests that enhanced replication stress and reduced DNA repair capacity are also major mechanisms of TTFields effects, effects for which there are therapeutic implications.
肿瘤治疗电场（TTFields）是一种非侵入性的癌症治疗物理模式，它向肿瘤施加低强度、中频和交变电场。有丝分裂干扰是描述 TTFields 对癌细胞影响的第一个机制；然而，TTFields 不仅被证明可以减少辐射诱导的 DNA 双链断裂（DSB）的重新连接，而且还可以诱导 DNA DSB。TTFields 产生 DNA DSB 的机制与复制应激的产生有关，包括 DNA 复制复合物基因 MCM6 和 MCM10 的表达减少以及范可尼贫血途径基因的表达减少。当由于 TTFields 暴露而产生的 DNA 复制应激标志物被检查时，新复制的 DNA 长度随着 TTFields 暴露时间的延长而减少，并且 R 环形成增加。此外，随着细胞暴露于 TTFields，形成了条件脆弱性环境，使细胞更容易受到 DNA 损伤剂或干扰 DNA 修复或复制叉维持的药物的影响。TTFields 暴露同时暴露于顺铂或 PARP 抑制剂、TTFields 加同时 PARP 抑制剂加随后的辐射、或 TTFields 暴露结束时单独的辐射的效果均具有协同作用。最后，对 47 个关键有丝分裂调节剂基因的基因表达分析表明，TTFields 诱导的有丝分裂异常和 DNA 损伤/复制应激事件虽然彼此密切相关，但很可能彼此独立地开始。这表明增强的复制应激和降低的 DNA 修复能力也是 TTFields 作用的主要机制，这些作用具有治疗意义。
