Nguyen J T, Wu P, Clouse M E, Hlatky L, Terwilliger E F
Department of Radiological Sciences, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Cancer Res. 1998 Dec 15;58(24):5673-7.
Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.
抗血管生成肿瘤疗法因其广谱作用、低毒性，以及在直接靶向内皮细胞时不存在耐药性，最近引起了广泛关注。为了促进肿瘤消退并维持休眠状态，抗血管生成药物需要长期给药。基因治疗提供了一种实现强效抗血管生成物质持续治疗性释放的潜在方法。作为朝着这个目标迈出的一步，我们构建了重组腺相关病毒（rAAV）载体，其携带编码血管抑素、内皮抑素以及针对血管内皮生长因子（VEGF）的反义mRNA的基因。这些rAAV有效地转导了所测试的三种人类肿瘤细胞系。用编码反义VEGF mRNA的rAAV进行转导可抑制内源性肿瘤细胞VEGF的产生。用这种rAAV或表达内皮抑素或血管抑素的rAAV转导的细胞的条件培养基在体外抑制了毛细血管内皮细胞的增殖。抗血管生成rAAV可能为破坏肿瘤新生血管形成和癌症进展提供一种新的基因治疗方法。
