Inhibition of neovascularization and tumor growth, and facilitation of wound repair, by halofuginone, an inhibitor of collagen type I synthesis.
Halofuginone, an inhibitor of collagen alpha1(I) gene expression was used for the treatment of subcutaneously implanted C6 glioma tumors. Halofuginone had no effect on the growth of C6 glioma spheroids in vitro, and these spheroids showed no collagen alpha1(I) expression and no collagen synthesis. However, a significant attenuation of tumor growth was observed in vivo, for spheroids implanted in CD-1 nude mice which were treated by oral or intraperitoneal (4 microg every 48 hours) administration of halofuginone. In these mice, treatment was associated with a dose-dependent reduction in collagen alpha1(I) expression and dose- and time-dependent inhibition of angiogenesis, as measured by MRI. Moreover, halofuginone treatment was associated with improved re-epithelialization of the chronic wounds that are associated with this experimental model. Oral administration of halofuginone was effective also in intervention in tumor growth, and here, too, the treatment was associated with reduced angiogenic activity and vessel regression. These results demonstrate the important role of collagen type I in tumor angiogenesis and tumor growth and implicate its role in chronic wounds. Inhibition of the expression of collagen type I provides an attractive new target for cancer therapy.
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
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R
Abramovitch
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Dafni
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M
Neeman
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Nagler
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Pines
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D017403:In Situ Hybridization; D007700:Kinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D010880:Piperidines; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects*
D000970:Antineoplastic Agents; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; D003094:Collagen; C010176:halofuginone