Schmidt Nils Ole, Ziu Mateo, Carrabba Giorgio, Giussani Carlo, Bello Lorenzo, Sun Yanping, Schmidt Karl, Albert Mitchel, Black Peter Mcl, Carroll Rona S
Department of Neurosurgery, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Clin Cancer Res. 2004 Feb 15;10(4):1255-62. doi: 10.1158/1078-0432.ccr-03-0052.
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.
靶向活跃的血管生成（这是恶性胶质瘤的一个主要标志）是一种潜在的治疗方法。为了有效抑制肿瘤诱导的新生血管形成，抗血管生成化合物必须在一段持续时间内以足够的量进行递送。许多抗血管生成抑制剂的短生物半衰期以及肿瘤内血流受损造成了后勤方面的困难，这使得有必要优化药物递送以治疗恶性胶质瘤。在本研究中，我们比较了通过每日全身给药或局部脑内微量注射递送内皮抑素对裸鼠体内已建立的颅内U87人胶质母细胞瘤异种移植物的影响。使用非侵入性磁共振成像方法评估治疗效果，并对肿瘤体积、微血管密度、增殖和凋亡率进行了额外的组织病理学分析。连续三周局部脑内微量注射内皮抑素（2毫克/千克/天）导致肿瘤体积减少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）。全身给予剂量高10倍的内皮抑素（20毫克/千克/天），尽管微血管密度显著降低（26.9%，P<0.005），但并未导致肿瘤体积减小，也未使肿瘤细胞凋亡增加。磁共振成像被用于成功证明治疗效果。当以2毫克/千克/天的剂量给予人内皮抑素时，局部微量注射显著提高了存活率，当剂量增加到12毫克/千克/天时长进一步延长。我们的结果表明，局部脑内微量注射抗血管生成化合物是克服抑制胶质瘤诱导的血管生成的后勤问题的有效方法。
