Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the Sleeping Beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma
Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the Sleeping Beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma
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DOI：
10.1016/j.ymthe.2005.07.689
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发表时间：
2005-11-01
影响因子：
12.4
通讯作者：
Largaespada, DA
中科院分区：
文献类型：
--
作者：
Ohlfest, JR;Demorest, ZL;Largaespada, DA
胶质母细胞瘤是一种致命的脑肿瘤，通过分泌促血管生成因子而变得高度血管化，并依赖于持续的血管生成来增加大小。因此，一种成功的抗血管生成治疗应该提供对肿瘤诱导的血管生成的长期抑制，这表明长期基因转移是一种治疗策略。在这项研究中，可溶性血管内皮生长因子受体（sFlt-1）和血管他汀-内皮抑制素融合基因（他汀- ae）通过非病毒基因转移使用睡美人（SB）转座子共传递到人胶质母细胞瘤异种移植物。在皮下植入的异种移植物中，两种转基因共同注射显示出明显的抗肿瘤活性，表现为肿瘤血管密度降低，抑制或消除胶质瘤生长，提高动物存活率（P = 0.003）。采用荧光素酶体内显像技术，对以对流增强方式向肿瘤内传递质粒DNA的抗肿瘤效果进行了评价。只有当他汀- ae和sFlt-1转座子与包含sb转座酶的DNA共同使用以促进长期表达时，才能实现颅内胶质瘤的持续肿瘤消退。我们发现SB可以通过联合抗血管生成基因转移在颅内胶质瘤模型中显著提高动物存活率（P = 0.008）。
Glioblastoma is a fatal brain tumor that becomes highly vascularized by secreting proangiogenic factors and depends on continued angiogenesis to increase in size. Consequently, a successful antiangiogenic therapy should provide long-term inhibition of tumor-induced angiogenesis, suggesting long-term gene transfer as a therapeutic strategy. In this study a soluble vascular endothelial growth factor receptor (sFlt-1) and an angiostatin-endostatin fusion gene (statin-AE) were codelivered to human glioblastoma xenografts by nonviral gene transfer using the Sleeping Beauty (SB) transposon. In subcutaneously implanted xenografts, co-injection of both transgenes showed marked anti-tumor activity as demonstrated by reduction of tumor vessel density, inhibition or abolition of glioma growth, and increase in animal survival (P = 0.003). Using luciferase-stable engrafted intracranial gliomas, the anti-tumor effect of convection-enhanced delivery of plasmid DNA into the tumor was assessed by luciferase in vivo imaging. Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were coadministered with SB-transposase-encocling DNA to facilitate long-term expression. We show that SB can be used to increase animal survival significantly (P = 0.008) by combinatorial antiangiogenic gene transfer in an intracranial glioma model.