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抗血管内皮生长因子治疗作为一种治疗神经纤维瘤病相关肿瘤的新方法。

Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors.

机构信息

Department of Radiation Oncology, Steele Laboratory, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

出版信息

Cancer Res. 2010 May 1;70(9):3483-93. doi: 10.1158/0008-5472.CAN-09-3107. Epub 2010 Apr 20.

Abstract

Patients with bilateral vestibular schwannomas associated with neurofibromatosis type 2 (NF2) experience significant morbidity such as complete hearing loss. We have recently shown that treatment with bevacizumab provided tumor stabilization and hearing recovery in a subset of NF2 patients with progressive disease. In the current study, we used two animal models to identify the mechanism of action of anti-vascular endothelial growth factor (VEGF) therapy in schwannomas. The human HEI193 and murine Nf2(-/-) cell lines were implanted between the pia and arachnoid meninges as well as in the sciatic nerve to mimic central and peripheral schwannomas. Mice were treated with bevacizumab (10 mg/kg/wk i.v.) or vandetanib (50 mg/kg/d orally) to block the VEGF pathway. Using intravital and confocal microscopy, together with whole-body imaging, we measured tumor growth delay, survival rate, as well as blood vessel structure and function at regular intervals. In both models, tumor vessel diameter, length/surface area density, and permeability were significantly reduced after treatment. After 2 weeks of treatment, necrosis in HEI193 tumors and apoptosis in Nf2(-/-) tumors were significantly increased, and the tumor growth rate decreased by an average of 50%. The survival of mice bearing intracranial schwannomas was extended by at least 50%. This study shows that anti-VEGF therapy normalizes the vasculature of schwannoma xenografts in nude mice and successfully controls the tumor growth, probably by reestablishing a natural balance between VEGF and semaphorin 3 signaling.

摘要

患有双侧听神经鞘瘤并伴有神经纤维瘤病 2 型(NF2)的患者会出现严重的发病情况,例如完全失聪。我们最近发现,贝伐单抗治疗可使部分进展性 NF2 患者的肿瘤稳定并恢复听力。在当前的研究中,我们使用了两种动物模型来确定抗血管内皮生长因子(VEGF)治疗在听神经鞘瘤中的作用机制。人 HEI193 和鼠 Nf2(-/-)细胞系被植入软脑膜和蛛网膜之间以及坐骨神经中,以模拟中枢和外周听神经鞘瘤。小鼠接受贝伐单抗(10mg/kg/周静脉注射)或凡德他尼(50mg/kg/天口服)治疗以阻断 VEGF 通路。通过使用活体和共聚焦显微镜以及全身成像,我们定期测量肿瘤生长延迟、存活率以及血管结构和功能。在这两种模型中,肿瘤血管直径、长度/表面积密度和通透性在治疗后均显著降低。治疗 2 周后,HEI193 肿瘤中的坏死和 Nf2(-/-)肿瘤中的凋亡明显增加,肿瘤生长速度平均降低了 50%。颅内听神经鞘瘤小鼠的存活率至少延长了 50%。这项研究表明,抗 VEGF 治疗可使裸鼠异种移植的听神经鞘瘤血管正常化,并成功控制肿瘤生长,这可能是通过重新建立 VEGF 和 Sema3 信号之间的自然平衡来实现的。

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