Abstract
A majority of human colon carcinomas coexpress the epidermal growth factor (EGF)-related peptides transforming growth factor alpha (TGFalpha), amphiregulin (AR) and CRIPTO-1 (CR). We have synthesized novel, antisense mixed backbone oligonucleotides (AS MBOs) directed against TGFalpha, AR and CR. We screened the EGF-related AS MBOs for their ability to inhibit the anchorage independent growth of GEO human colon carcinoma cells. The MBOs that showed a high in vitro efficacy were then used for in vivo experiments. TGFalpha, AR and CR AS MBOs were able to inhibit the growth of GEO tumor xenografts in nude mice in a dose-dependent manner. Furthermore, the AS MBOs were able to specifically inhibit the expression of the target mRNAs and proteins in the tumor xenografts. A more significant tumor growth inhibition was observed when mice were treated with a combination of the three AS MBOs as compared to treatment with a single AS MBO. Finally, tumors from mice treated with TGFalpha, AR and CR AS MBOs showed a significant reduction of microvessel count, as compared with tumors from untreated mice or from mice treated with a single AS MBO. These data suggest that combinations of AS oligonucleotides directed against different growth factors might represent a novel, experimental therapy approach of colon carcinomas.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amphiregulin
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Animals
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology*
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EGF Family of Proteins
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Epidermal Growth Factor*
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GPI-Linked Proteins
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Glycoproteins / antagonists & inhibitors*
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Glycoproteins / biosynthesis
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Glycoproteins / genetics
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Growth Inhibitors / genetics
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Growth Inhibitors / pharmacology
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Growth Substances / biosynthesis
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Growth Substances / genetics
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Humans
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Intercellular Signaling Peptides and Proteins*
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Membrane Glycoproteins*
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Mice
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Mice, Nude
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neovascularization, Pathologic / drug therapy
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Oligonucleotides, Antisense / genetics
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Oligonucleotides, Antisense / pharmacology*
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Thionucleotides / genetics
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Thionucleotides / pharmacology*
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Transforming Growth Factor alpha / antagonists & inhibitors*
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Transforming Growth Factor alpha / biosynthesis
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Transforming Growth Factor alpha / genetics
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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AREG protein, human
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Amphiregulin
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Areg protein, mouse
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EGF Family of Proteins
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GPI-Linked Proteins
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Glycoproteins
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Growth Inhibitors
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Growth Substances
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Intercellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Neoplasm Proteins
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Oligonucleotides, Antisense
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TDGF1 protein, human
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Tdgf1 protein, mouse
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Thionucleotides
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Transforming Growth Factor alpha
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Epidermal Growth Factor