Antitumor effect utilizing antiangiogenic activity by ribozyme

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It has been known that tumors require ongoing angiogenesis to support their growth. Inhibition of angiogenesis by production of antiangiogenic factors should be a viable approach for cancer gene therapy. Similarly, inhibition of angiogenic factor has an impact to suppress the tumor growth. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis and many studies have shown that VEGF is upregulated in many human tumors. We have planned to inhibit vascular VEGF receptors using ribozyme. However we have failed to produce the vector to secrete ribozyme to inhibit VEGF receptors. Instead of that, we have turned our attention to RNA interference. RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. The strategy to regulate the tumor angiogenesis with the ribozyme targeted VEGF in tumor cell was changed to it with RNAi technique. We investigated the silencing effect of small interfering RNA (siRNA) duplexes targeting the gene VEGF-receptor (VEGFR) in vascular endothelial cell to inhibit its activity of angiogenesis and evaluated its effect against to the tumor progression in vivo model. We optimized the RNAi target sequence of VEGFR-1. Trasfection of VEGFR-1 siRNA to vascular endothelial cell specially reduced VEGFR-1 expression. Further, the RANi target sequence to VEGFR-2 was optimized and the shRNA targeted to VEGFR-2 expression vector was constructed. Now we plan to evaluate this powerful utility in in vivo model.