Department of Radiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China; Department of Radiology, Washington University, St Louis, Missouri.
Department of Chemistry, Washington University, St Louis, Missouri.
Int J Radiat Oncol Biol Phys. 2018 Mar 15;100(4):1016-1025. doi: 10.1016/j.ijrobp.2017.12.257. Epub 2017 Dec 21.
There is mounting evidence that, in addition to angiogenesis, hypoxia-induced inflammation via the hypoxia-inducible factor 1α (HIF-1α)-CXC chemokine receptor 4 (CXCR4) pathway may contribute to the pathogenesis of late-onset, irradiation-induced necrosis. This study investigates the mitigative efficacy of an HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis (RN) in an intracranial mouse model.
Mice received a single-fraction, 50-Gy dose of hemispheric irradiation from the Leksell Gamma Knife Perfexion and were then treated with either topotecan, an HIF-1α inhibitor, from 1 to 12 weeks after irradiation, or AMD3100, a CXCR4 antagonist, from 4 to 12 weeks after irradiation. The onset and progression of RN were monitored longitudinally via noninvasive, in vivo magnetic resonance imaging (MRI) from 4 to 12 weeks after irradiation. Conventional hematoxylin-eosin staining and immunohistochemistry staining were performed to evaluate the treatment response.
The progression of brain RN was significantly mitigated for mice treated with either topotecan or AMD3100 compared with control animals. MRI-derived lesion volumes were significantly smaller for both of the treated groups, and histologic findings correlated well with the MRI data. By hematoxylin-eosin staining, both treated groups demonstrated reduced irradiation-induced tissue damage compared with controls. Furthermore, immunohistochemistry results revealed that expression levels of vascular endothelial growth factor, CXC chemokine ligand 12, CD68, CD3, and tumor necrosis factor α in the lesion area were significantly lower in treated (topotecan or AMD3100) brains versus control brains, while ionized calcium-binding adapter molecule 1 (Iba1) and HIF-1α expression was similar, though somewhat reduced. CXCR4 expression was reduced only in topotecan-treated mice, while interleukin 6 expression was unaffected by either topotecan or AMD3100.
By reducing inflammation, both topotecan and AMD3100 can, independently, mitigate the development of RN in the mouse brain. When combined with first-line, antiangiogenic treatment, anti-inflammation therapy may provide an adjuvant therapeutic strategy for clinical, postirradiation management of tumors, with additional benefits in the mitigation of RN development.
越来越多的证据表明，除了血管生成外，缺氧诱导因子 1α（HIF-1α）-CXC 趋化因子受体 4（CXCR4）通路诱导的炎症可能有助于迟发性、照射诱导的坏死的发病机制。本研究旨在探讨 HIF-1α 抑制剂拓扑替康和 CXCR4 拮抗剂 AMD3100 对颅内小鼠模型中放射性坏死（RN）发展的缓解作用。
小鼠接受单次 50Gy 半脑照射，然后在照射后 1 至 12 周内接受拓扑替康（HIF-1α 抑制剂）治疗，或在照射后 4 至 12 周内接受 AMD3100（CXCR4 拮抗剂）治疗。从照射后 4 至 12 周，通过非侵入性、体内磁共振成像（MRI）对 RN 的发生和进展进行纵向监测。用常规苏木精-伊红染色和免疫组织化学染色来评估治疗反应。
与对照组相比，接受拓扑替康或 AMD3100 治疗的小鼠的脑 RN 进展明显减轻。两种治疗组的 MRI 测量的病变体积明显较小，组织学发现与 MRI 数据很好地相关。苏木精-伊红染色显示，与对照组相比，两组治疗组的照射诱导的组织损伤均减少。此外，免疫组织化学结果显示，在病变区域中，血管内皮生长因子、CXC 趋化因子配体 12、CD68、CD3 和肿瘤坏死因子-α的表达水平在治疗（拓扑替康或 AMD3100）脑与对照脑中显著降低，而离子钙结合接头分子 1（Iba1）和 HIF-1α 的表达相似，但略有降低。CXCR4 表达仅在接受拓扑替康治疗的小鼠中降低，而白细胞介素 6 的表达不受拓扑替康或 AMD3100 的影响。
通过减少炎症，拓扑替康和 AMD3100 都可以独立地减轻小鼠大脑中 RN 的发展。当与一线抗血管生成治疗相结合时，抗炎治疗可能为肿瘤放射治疗后的临床管理提供一种辅助治疗策略，在减轻 RN 发展方面具有额外的益处。
