Antiangiogenic therapy by local intracerebral microinfusion improves treatment efficiency and survival in an orthotopic human glioblastoma model
Antiangiogenic therapy by local intracerebral microinfusion improves treatment efficiency and survival in an orthotopic human glioblastoma model
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DOI：
10.1158/1078-0432.ccr-03-0052
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发表时间：
2004-02-15
影响因子：
11.5
通讯作者：
Carroll, RS
中科院分区：
文献类型：
--
作者：
Schmidt, NO;Ziu, M;Carroll, RS
针对活跃的血管生成是一种潜在的治疗方法，这是恶性神经胶质瘤的主要标志。为了有效抑制肿瘤诱导的新血管形成，必须在持续的时间内递送足够量的抗血管生成化合物。许多抗血管生成抑制剂的生物半衰期短和瘤内血流受损造成了后勤困难，因此有必要优化治疗恶性神经胶质瘤的药物输送。在这项研究中，我们比较了通过每日全身给药或局部脑内微量输注递送的内皮抑素对在裸鼠中建立的颅内U87人胶质母细胞瘤异种移植物的影响。使用无创磁共振成像方法评估治疗效果，并对肿瘤体积、微血管密度、增殖和凋亡率进行额外的组织病理学分析。局部脑内微量输注内皮抑素（2 mg/kg/天）三周后，肿瘤体积缩小了 74%（P < 0.05），微血管密度降低（33.5%，P < 0.005），肿瘤细胞凋亡增加 3 倍（P < 0.002）。尽管微血管密度显着降低（26.9%，P < 0.005），但全身施用10倍高量的内皮抑素（20 mg/kg/天）并没有导致肿瘤体积减小，也没有导致肿瘤细胞凋亡增加。使用磁共振成像成功证明了治疗效果。当以 2 mg/kg/天给药时，人内皮抑素的局部微量输注显着提高了存活率，并且当剂量增加到 12 mg/kg/天时，存活率进一步延长。我们的结果表明，抗血管生成化合物的局部脑内微量输注是克服抑制神经胶质瘤诱导的血管生成的后勤问题的有效方法。
Targeting active angiogenesis, which is a major hallmark of malignant gliomas, is a potential therapeutic approach. For effective inhibition of tumor-induced neovascularization, antiangiogenic compounds have to be delivered in sufficient quantities over a sustained period of time. The short biological half-life of many antiangiogenic inhibitors and the impaired intratumoral blood flow create logistical difficulties that make it necessary to optimize drug delivery for the treatment of malignant gliomas. In this study, we compared the effects of endostatin delivered by daily systemic administration or local intracerebral microinfusion on established intracranial U87 human glioblastoma xenografts in nude mice. Noninvasive magnetic resonance imaging methods were used to assess treatment effects and additional histopathological analysis of tumor volume, microvessel density, proliferation, and apoptosis rate were performed. Three weeks of local intracerebral microinfusion of endostatin (2 mg/kg/day) led to 74% (P < 0.05) reduction of tumor volumes with decreased microvessel densities (33.5%, P < 0.005) and a 3-fold increased tumor cell apoptosis (P < 0.002). Systemic administration of a 10-fold higher amount of endostatin (20 mg/kg/day) did not result in a reduction of tumor volume nor in an increase of tumor cell apoptosis despite a significant decrease of microvessel densities (26.9%, P < 0.005). Magnetic resonance imaging was used to successfully demonstrate treatment effects. The local microinfusion of human endostatin significantly increased survival when administered at 2 mg/kg/day and was prolonged further when the dose was increased to 12 mg/kg/day. Our results indicate that the local intracerebral microinfusion of antiangiogenic compounds is an effective way to overcome the logistical problems of inhibiting glioma-induced angiogenesis.