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, 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.
Abounader
Roger
R
Johns Hopkins University School of Medicine, Department of Neurology, Kennedy Krieger Research Institute, Baltimore, Maryland, USA.
Lal
Bachchu
B
Luddy
Carey
C
Koe
Gary
G
Davidson
Beverly
B
Rosen
Eliot M
EM
Laterra
John
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D002455:Cell Division; D016373:DNA, Antisense / Q000008:administration & dosage; D005822:Genetic Vectors; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D016337:RNA, Catalytic / Q000235:genetics*; D012334:RNA, Neoplasm / Q000032:analysis; D012342:RNA, Small Nuclear / Q000235:genetics*; D019076:Transgenes; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D016373:DNA, Antisense; D016337:RNA, Catalytic; D012334:RNA, Neoplasm; D012342:RNA, Small Nuclear; C405483:U1 small nuclear RNA; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met