Molecular Medicine (Oct 2013)
Antiangiogenic and Antitumoral Effects Mediated by a Vascular Endothelial Growth Factor Receptor 1 (VEGFR-1)-Targeted DNAzyme
Abstract
Abstract Antiangiogenesis is a promising antitumor strategy that inhibits tumor vascular formation to suppress tumor growth. DNAzymes are synthetic single-strand deoxyribonucleic acid (DNA) molecules that can cleave ribonucleic acids (RNAs). Here, we conducted a comprehensive in vitroselection of active DNAzymes for their activity to cleave the vascular endothelial growth factor receptor (VEGFR-1) mRNA and screened for their biological activity in a matrigel tube-formation assay. Among the selected DNAzymes, DT18 was defined as a lead molecule that was further investigated in several model systems. In a rat corneal vascularization model, DT18 demonstrated significant and specific antiangiogenic activity, as evidenced by the reduced area and vessel number in VEGF-induced corneal angiogenesis. In a mouse melanoma model, DT18 was shown to inhibit B16 tumor growth, whereas it did not affect B16 cell proliferation. We further assessed the DT18 effect in mice with established human nasopharyngeal carcinoma (NPC). A significant inhibition of tumor growth was observed, which accompanied downregulation of VEGFR-1 expression in NPC tumor tissues. To evaluate DT18 effect on vasculature, we performed dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) on the human NPC xenograft mice treated with DT18 and showed a reduction of the parameter of Ktrans (volume constant for transfer of contrast agent), which reflects the condition of tumor microvascular permeability. When examining the safety and tolerability of DT18, intravenous administration of Dz18 to healthy mice caused no substantial toxicities, as shown by parameters such as body weight, liver/kidney function, and histological and biochemical analyses. Taken together, our data suggest that the anti-VEGFR-1DNAzyme may be used as a therapeutic agent for the treatment of cancer, such as NPC.
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