Pfeifer A, Kessler T, Silletti S, Cheresh D A, Verma I M
The Salk Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12227-32. doi: 10.1073/pnas.220399597.
Modulation of the balance between pro- and antiangiogenic factors holds great promise for the treatment of a broad spectrum of human disease ranging from ischemic heart disease to cancer. This requires both the identification of angiogenic regulators and their efficient delivery to target organs. Here, we demonstrate the use of a noncatalytic fragment of matrix metalloproteinase 2 (termed PEX) delivered by lentiviral vectors in different angiogenesis models. Transduction of human endothelial cells with PEX virus suppressed endothelial invasion and formation of capillary-like structures without affecting chemotaxis in vitro. Lentiviral delivery of PEX blocked basic fibroblast growth factor-induced matrix metalloproteinase 2 activation and angiogenesis on chicken chorioallantoic membranes. PEX expression also inhibited tumor-induced angiogenesis and tumor growth in a nude mouse model. Thus, our study shows that lentiviral vectors can deliver sufficient quantities of antiangiogenic substances to achieve therapeutic effects in vivo.
调节促血管生成因子和抗血管生成因子之间的平衡，对于治疗从缺血性心脏病到癌症等广泛的人类疾病具有巨大潜力。这既需要鉴定血管生成调节因子，又需要将它们有效地递送至靶器官。在此，我们展示了在不同的血管生成模型中，使用慢病毒载体递送基质金属蛋白酶2的非催化片段（称为PEX）。用PEX病毒转导人内皮细胞可抑制内皮细胞侵袭和毛细管样结构的形成，而不影响体外趋化性。在鸡胚绒毛尿囊膜上，PEX的慢病毒递送可阻断碱性成纤维细胞生长因子诱导的基质金属蛋白酶2激活和血管生成。在裸鼠模型中，PEX表达还可抑制肿瘤诱导的血管生成和肿瘤生长。因此，我们的研究表明，慢病毒载体能够递送足量的抗血管生成物质，以在体内实现治疗效果。
