In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis

The multifunctional growth factor scatter factor/hepatocyte growth factor ( SF/HGF) and its receptor c-met have been implicated in the genesis, maligna nt progression, and chemo/radioresistance of multiple human malignancies, i ncluding gliomas. We examined the antitumor effects of targeting SF/HGF and c-met expression in pre-established glioma xenografts by using novel chime ric U1snRNA/ribozymes. Transient expression of anti-SF/HGF and anti-c-met U 1snRNA/ribozymes inhibited SF/HGF and c-met expression, c-met receptor acti vation, tumor cell migration, and anchorage-independent colony formation in vitro. Delivery of U1snRNA/ribozymes to established subcutaneous glioma xe nografts via liposome-DNA complexes significantly inhibited tumor growth as well as tumor SF/HGF and c-met expression levels. Histologic analysis of t umors treated with U1snRNA/ribozymes showed a significant decrease in blood vessel density, an increase in activation of the pro-apoptotic enzyme casp ase-3, and an increase in tumor cell apoptosis. Treatment of animals bearin g intracranial glioma xenografts with anti-SF/HGF and anti-c-met U1snRNA/ri bozymes by either intratumoral injections of adenoviruses expressing the tr ansgenes or intravenous injections of U1snRNA/ribozyme-liposome complexes s ubstantially inhibited tumor growth and promoted animal survival. We demons trate that SF/HGF and/ or c-met expression can be targeted in vivo to inhib it tumor growth. In addition, our findings represent the first in vivo appl ication of chimeric U1snRNA/ribozymes, which have numerous potential therap eutic gene-targeting applications.