Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence.
Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence.
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DOI：
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发表时间：
1996-01
期刊：
影响因子：
11.2
通讯作者：
M. Saleh;S. Stacker;A. Wilks
中科院分区：
文献类型：
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作者：
M. Saleh;S. Stacker;A. Wilks
肿瘤血管生成涉及一系列事件的组合，包括产生对内皮细胞具有趋化和促有丝分裂作用的抑制剂、蛋白酶和血管生成因子。血管内皮生长因子（VEGF）是一种内皮细胞特异性有丝分裂原，可促进实体瘤（包括脑肿瘤，如星形细胞瘤）的血管生成。作为开发脑肿瘤基因治疗新策略的一种方法，我们中断了VEGF/VEGF受体旁分泌途径，试图抑制血管生成，从而控制肿瘤生长。用反义VEGF cDNA真核表达载体转染大鼠C6胶质瘤细胞。在低氧条件下，观察到稳定的转染子在培养物中表达降低水平的VEGF。当皮下植入时在裸（nu/nu）小鼠中，观察到反义VEGF细胞系的生长与对照细胞相比被极大地抑制，尽管它们在体外具有更快的分裂时间。对这些肿瘤的分析表明，它们具有更少的血管和更高程度的坏死，这是肿瘤尺寸减小的合理解释。我们相信反义VEGF可以成功地用于控制肿瘤生长，并可能为抗血管生成基因治疗的发展提供基础。
Tumor angiogenesis involves a combination of events including the production of inhibitors, proteases, and angiogenic factors that have a chemotactic and mitogenic effect on endothelial cells. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that promotes angiogenesis in solid tumors, including brain tumors such as astrocytomas. As an approach to the development of new strategies for gene therapy of brain tumors, we have interrupted the VEGF/VEGF receptor paracrine pathway in an attempt to inhibit angiogenesis and thereby control tumor growth. Rat C6 glioma cells were transfected with a eukaryotic expression vector bearing an antisense-VEGF cDNA. Stable transfectants were observed to express reduced levels of VEGF in culture under hypoxic conditions. When implanted s.c. into nude (nu/nu) mice, growth of the antisense-VEGF cell lines was observed to be greatly inhibited compared to control cells, despite the fact that they have a faster division time in vitro. Analysis of these tumors revealed that they have fewer blood vessels and a higher degree of necrosis, which is a plausible explanation for the reduced tumor size. We believe antisense-VEGF can be successfully used to control tumor growth and may provide the basis for the development of antiangiogenic gene therapy.