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Inhibitors of HIF-1? and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain.

ABSTRACT: PURPOSE:There is mounting evidence that, in addition to angiogenesis, hypoxia-induced inflammation via the hypoxia-inducible factor 1? (HIF-1?)-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-1? inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis (RN) in an intracranial mouse model. METHODS AND MATERIALS: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-1? 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. RESULTS: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 ? 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-1? 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. CONCLUSIONS: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.

SUBMITTER: Yang R

PROVIDER: S-EPMC6389273 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Inhibitors of HIF-1α and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain.

Yang Ruimeng R Yang Ruimeng R Duan Chong C Yuan Liya L Engelbach John A JA Tsien Christina I CI Beeman Scott C SC Perez-Torres Carlos J CJ Ge Xia X Rich Keith M KM Ackerman Joseph J H JJH Garbow Joel R JR

International journal of radiation oncology, biology, physics 20171221 4

<h4>Purpose</h4>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.<h4>Methods and materials</h4>Mice ...[more]

PMID: 29485043

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Project description:Background: Current imaging-based discrimination between radiation necrosis versus recurrent glioblastoma contrast-enhancing lesions remains imprecise but is paramount for prognostic and therapeutic evaluation. We examined whether patients with radiation necrosis exhibit distinct patterns of blood oxygenation-level dependent fMRI cerebrovascular reactivity (BOLD-CVR) as the first step to better distinguishing patients with radiation necrosis from recurrent glioblastoma compared with patients with newly diagnosed glioblastoma before surgery and radiotherapy. Methods: Eight consecutive patients with primary and secondary brain tumors and a multidisciplinary clinical and radiological diagnosis of radiation necrosis, and fourteen patients with a first diagnosis of glioblastoma underwent BOLD-CVR mapping. For all these patients, the contrast-enhancing lesion was derived from high-resolution T1-weighted MRI and rendered the volume-of-interest (VOI). From this primary VOI, additional 3 mm concentric expanding VOIs up to 30 mm were created for a detailed perilesional BOLD-CVR tissue analysis between the two groups. Receiver operating characteristic curves assessed the discriminative properties of BOLD-CVR for both groups. Results: Mean intralesional BOLD-CVR values were markedly lower in radiation necrosis than in glioblastoma contrast-enhancing lesions (0.001 ± 0.06 vs. 0.057 ± 0.05; p = 0.04). Perilesionally, a characteristic BOLD-CVR pattern was observed for radiation necrosis and glioblastoma patients, with an improvement of BOLD-CVR values in the radiation necrosis group and persisting lower perilesional BOLD-CVR values in glioblastoma patients. The ROC analysis discriminated against both groups when these two parameters were analyzed together (area under the curve: 0.85, 95% CI: 0.65-1.00). Conclusions: In this preliminary analysis, distinctive intralesional and perilesional BOLD-cerebrovascular reactivity patterns are found for radiation necrosis.

Project description:BackgroundRadiation brain necrosis (RBN) is a serious complication in patients receiving radiotherapy for intracranial disease. Many studies have investigated the efficacy and safety of bevacizumab in patients with RBN. In the present study, we systematically reviewed the medical literature for studies reporting the efficacy and safety of bevacizumab, as well as for studies comparing bevacizumab with corticosteroids.Materials and methodsWe searched PubMed, Cochrane library, EMBASE, and ClinicalTrials.gov from their inception through 1 March, 2020 for studies that evaluated the efficacy and safety of bevacizumab in patients with RBN. Two investigators independently performed the study selection, data extraction, and data synthesis.ResultsOverall, the present systematic review included 12 studies (eight retrospective, two prospective, and two randomized control trials [RCTs]) involving 236 patients with RBN treated who were treated with bevacizumab. The two RCTs also had control arms comprising patients with RBN who were treated with corticosteroids/placebo (n=57). Radiographic responses were recorded in 84.7% (200/236) of patients, and radiographic progression was observed in 15.3% (36/236). Clinical improvement was observed in 91% (n=127) of responding patients among seven studies (n=113). All 12 studies reported volume reduction on T1 gadolinium enhancement MRI (median: 50%, range: 26%-80%) and/or T2 FLAIR MRI images (median: 59%, range: 48%-74%). In total, 46 responding patients (34%) had recurrence. The two RCTs revealed significantly improved radiographic response in patients treated with bevacizumab (Levin et al.: p = 0.0013; Xu et al.: p < 0.001). Both also showed clinical improvement (Levin et al.: NA; Xu et al.: p = 0.039) and significant reduction in edema volume on both T1 gadolinium enhancement MRI (Levin et al.: p=0.0058; Xu et al.: p=0.027) and T2 FLAIR MRI (Levin et al.: p=0.0149; Xu et al.: p < 0.001). Neurocognitive improvement was significantly better after 2 months of treatment in patients receiving bevacizumab than in those given corticosteroids, as assessed by the MoCA scale (p = 0.028). The recurrence rate and side effects of the treatments showed no significant differences.ConclusionsPatients with RBN respond to bevacizumab, which can improve clinical outcomes and cognitive function. Bevacizumab appears to be more efficacious than corticosteroid-based treatment. The safety profile was comparable to that of the corticosteroids.

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Inhibitors of HIF-1? and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain.

Publications

Inhibitors of HIF-1α and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain.

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