Cancer Research AACR Conference on Molecular Diagnostics - 2008 AACR Conference on Molecular Diagnostics - 2008
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[Cancer Research 62, 5463-5469, October 1, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

Angiogenic Inhibition Mediated by a DNAzyme That Targets Vascular Endothelial Growth Factor Receptor 21

Lei Zhang, Warren J. Gasper, Sanford A. Stass, Olga B. Ioffe, Myrtle A. Davis and A. James Mixson2

Department of Pathology [L. Z., W. S. G., S. A. S., O. B. I., M. A. D., A. J. M.] and Greenebaum Cancer Center [S. A. S., O. B. I., M. A. D., A. J. M.], University of Maryland Baltimore, Baltimore, Maryland 21201

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.




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Copyright © 2002 by the American Association for Cancer Research.