Angiogenic inhibition mediated by a DNAzyme that targets vascular endothelial growth factor receptor 2.
Angiogenic inhibition mediated by a DNAzyme that targets vascular endothelial growth factor receptor 2.
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发表时间：
2002-10
期刊：
影响因子：
11.2
通讯作者：
Lei Zhang;W. Gasper;S. Stass;O. Ioffe;Myrtle A. Davis;A. J. Mixson
中科院分区：
文献类型：
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作者：
Lei Zhang;W. Gasper;S. Stass;O. Ioffe;Myrtle A. Davis;A. J. Mixson
血管内皮生长因子受体（VEGFR）是肿瘤基因治疗的重要靶点。在这项研究中，我们设计了一种靶向VEGF受体2（VEGFR 2）转录物的mRNA切割寡核苷酸（VEGFR 2 DNAzyme）。发现该DNAzyme以浓度和时间依赖性方式有效地消化VEGFR 2的mRNA底物。我们还表明，与禁用的DNAzyme和未处理的对照组相比，DNAzyme诱导细胞凋亡，并显着抑制内皮细胞生长。相反，DNAzyme在体外不抑制MDA-MB-435细胞的生长。与非病毒载体复合的DNAzyme也显著抑制体内肿瘤生长。在第四次注射后，与盐水注射对照组相比，DNA酶治疗组的肿瘤大小减少了近75%（P = 0.024）。肿瘤周边区域的显著细胞死亡伴随着血管密度的降低与DNAzyme的抗血管生成机制一致。本研究表明，以肿瘤血管生成因子为靶点的DNA酶有望成为抗肿瘤药物。
The vascular endothelial growth factor receptor (VEGFR) is an important angiogenic target for cancer gene therapy. In this study, we designed an mRNA-cleaving oligodeoxynucleotide that targets the VEGF receptor 2 (VEGFR2) transcript (VEGFR2 DNAzyme). This DNAzyme was found to digest efficiently mRNA substrates of VEGFR2 in a concentration- and time-dependent manner. We also showed that the DNAzyme induces apoptosis and markedly inhibits endothelial cell growth compared with a disabled DNAzyme and untreated controls. In contrast, the DNAzyme did not inhibit the growth of MDA-MB-435 cells in vitro. The DNAzyme in complex with a nonviral carrier also significantly inhibited tumor growth in vivo. After the fourth injection, there was nearly a 75% reduction of tumor size in the DNAzyme-treated group compared with the saline-injected control group (P = 0.024). Marked cell death in the peripheral regions of the tumor accompanied by a reduction in blood vessel density is consistent with the antiangiogenic mechanism of the DNAzyme. This study indicates that DNAzymes, targeting angiogenic growth factors of tumors, show promise as antitumor agents.