Saleh M, Stacker S A, Wilks A F
Department of Surgery, University of Melbourne, Parksville, Victoria, Australia.
Cancer Res. 1996 Jan 15;56(2):393-401.
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.
肿瘤血管生成涉及一系列事件，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（包括星形细胞瘤等脑肿瘤）中的血管生成。作为开发脑肿瘤基因治疗新策略的一种方法，我们阻断了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。用携带反义VEGF cDNA的真核表达载体转染大鼠C6胶质瘤细胞。在缺氧条件下，观察到稳定转染子在培养物中表达的VEGF水平降低。当将其皮下植入裸（nu/nu）小鼠时，尽管反义VEGF细胞系在体外具有更快的分裂时间，但与对照细胞相比，其生长受到极大抑制。对这些肿瘤的分析表明，它们的血管较少且坏死程度较高，这是肿瘤体积减小的一个合理原因。我们认为反义VEGF可成功用于控制肿瘤生长，并可能为抗血管生成基因治疗的发展提供基础。
