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. 2002 Jan;16(1):108-10.
doi: 10.1096/fj.01-0421fje. Epub 2001 Nov 29.

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

Roger Abounader  1 , Bachchu Lal, Carey Luddy, Gary Koe, Beverly Davidson, Eliot M Rosen, John Laterra
Affiliations

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

Roger Abounader et al. FASEB J. 2002 Jan.

Abstract

The multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor c-met have been implicated in the genesis, malignant progression, and chemo/radioresistance of multiple human malignancies, including gliomas. We examined the antitumor effects of targeting SF/HGF and c-met expression in pre-established glioma xenografts by using novel chimeric U1snRNA/ribozymes. Transient expression of anti-SF/HGF and anti-c-met U1snRNA/ribozymes inhibited SF/HGF and c-met expression, c-met receptor activation, tumor cell migration, and anchorage-independent colony formation in vitro. Delivery of U1snRNA/ribozymes to established subcutaneous glioma xenografts via liposome-DNA complexes significantly inhibited tumor growth as well as tumor SF/HGF and c-met expression levels. Histologic analysis of tumors treated with U1snRNA/ribozymes showed a significant decrease in blood vessel density, an increase in activation of the pro-apoptotic enzyme caspase-3, and an increase in tumor cell apoptosis. Treatment of animals bearing intracranial glioma xenografts with anti-SF/HGF and anti-c-met U1snRNA/ribozymes by either intratumoral injections of adenoviruses expressing the transgenes or intravenous injections of U1snRNA/ribozyme-liposome complexes substantially inhibited tumor growth and promoted animal survival. We demonstrate that SF/HGF and/or c-met expression can be targeted in vivo to inhibit tumor growth. In addition, our findings represent the first in vivo application of chimeric U1snRNA/ribozymes, which have numerous potential therapeutic gene-targeting applications.

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