Angiogenic inhibition mediated by a DNAzyme that targets vascular endothelial growth factor receptor 2.
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.
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D021881:DNA, Catalytic / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D020533:Angiogenesis Inhibitors; D021881:DNA, Catalytic; D019394:Ki-67 Antigen; D009841:Oligonucleotides; D012333:RNA, Messenger; D040301:Vascular Endothelial Growth Factor Receptor-2