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

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.

• Authors: Roger Abounader, Bachchu Lal, Carey Luddy, Gary Koe, Beverly Davidson, Eliot M Rosen, John Laterra
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 16 Issue 1 Pg. 108-10 (Jan 2002) ISSN: 1530-6860 [Electronic] United States
• PMID: 11729097 (Publication Type: Journal Article)

Chemical References

• DNA, Antisense
• RNA, Catalytic
• RNA, Neoplasm
• RNA, Small Nuclear
• U1 small nuclear RNA
• Hepatocyte Growth Factor
• Proto-Oncogene Proteins c-met

Topics

• Adenoviridae (genetics)
• Animals
• Apoptosis
• Base Sequence
• Brain Neoplasms (pathology, therapy)
• Cell Division
• DNA, Antisense (administration & dosage)
• Genetic Vectors
• Glioblastoma (pathology, therapy)
• Hepatocyte Growth Factor (biosynthesis, genetics)
• Humans
• Mice
• Molecular Sequence Data
• Neovascularization, Pathologic
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• RNA, Catalytic (genetics)
• RNA, Neoplasm (analysis)
• RNA, Small Nuclear (genetics)
• Transgenes
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays