Szentirmai Oszkar, Baker Cheryl H, Bullain Szofia S, Lin Ning, Takahashi Masaya, Folkman Judah, Mulligan Richard C, Carter Bob S
Department of Genetics, Harvard Institutes of Medicine and Harvard Medical School, and Department of Pediatrics, Children's Hospital, Boston, MA, USA.
J Neurosurg. 2008 May;108(5):979-88. doi: 10.3171/JNS/2008/108/5/0979.
Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice.
Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control.
Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad-ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups.
These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM.
多形性胶质母细胞瘤（GBM）的特征是新生血管形成，这就引发了血管生成阻断是否可能成为该疾病有效治疗策略的问题。然而，有人提出，要想有效，血管生成阻断必须持续且达到足以克服肿瘤细胞促血管生成信号的水平。在本报告中，作者测试了这样一个假设，即使用全身基因治疗策略递送持续高浓度的两种不同抗血管生成蛋白，可抑制裸鼠体内已形成的颅内U87人GBM异种移植瘤的生长。
携带已形成U87颅内肿瘤的小鼠接受静脉注射腺病毒载体，分别为单独编码血管内皮生长因子受体-2-Fc融合蛋白（Ad-VEGFR2-Fc）胞外域的载体、单独的可溶性内皮抑素（Ad-ES）、Ad-VEGFR2-Fc与Ad-ES的组合，或作为对照的免疫球蛋白1-Fc（Ad-Fc）。
治疗三周后，基于磁共振成像测定肿瘤体积显示，Ad-VEGFR2-Fc、Ad-ES或Ad-VEGFR2-Fc与Ad-ES联合治疗分别产生了69%、59%和74%的生长抑制。对肿瘤生长的生物发光监测显示，相同治疗组的生长抑制分别为62%、74%和72%。用增殖细胞核抗原和末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记染色显示，所有抗血管生成治疗组的肿瘤细胞增殖减少，凋亡增加。
这些结果表明，内皮抑素和可溶性VEGFR2的全身递送和持续产生可通过减少细胞增殖和增加肿瘤凋亡来减缓颅内胶质肿瘤的生长。这项工作进一步支持了将抗血管生成疗法用于颅内GBM的概念。
