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Defibrotide, an Endothelium Protecting and Stabilizing Drug, Has Anti-Angiogenic Potential In Vitro and In Vivo
DF is a polydisperse mixture of single-stranded polydeoxyribunucleotides which is successfully used in the treatment of hepatic veno-occlusive disease and other endothelial disorders. Recent pre-clinical evidence suggests that DF might also have anti-neoplastic properties. We addressed the question...
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Published in: | Blood 2005-11, Vol.106 (11), p.3956-3956 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | DF is a polydisperse mixture of single-stranded polydeoxyribunucleotides which is successfully used in the treatment of hepatic veno-occlusive disease and other endothelial disorders. Recent pre-clinical evidence suggests that DF might also have anti-neoplastic properties. We addressed the question whether this might be due to the prevention of tumor blood vessel formation (angiogenesis). The anti-angiogeneic potential of DF was tested in vitro (Matrigel™ tube formation and aortic ring assay) and in vivo (dorsal skin-fold chamber model). Our results show that DF quantitatively (100%) blocks tube formation of trans-differentiated human endothelial-like cells (ELC) at concentrations corresponding to pharmacologic DF blood levels (100 μg/mL). Similarly, the sprouting of rat aorta endothelial cells in Matrigel™ was prevented by nearly 100%, when DF was applied on a daily basis. In vivo tumor angiogenesis in a human gastric cancer (TMK-1) grown in skin-fold chambers (nude mice) was also attenuated on day 5 by DF, as measured by microvascular density. Although the exact mechanism of DF action remains to be elucidated, initial Western blotting results show that DF reduces phosphorylation-activation of p70S6 kinase, which is a key target in the PI3K/Akt/mTOR signaling pathway linked to endothelial cell and pericyte proliferation and activation. Taken together, our data suggest that while DF is known for its endothelium-protecting function, it also inhibits tumor blood vessel formation, and thus should be considered for further testing as an anticancer agent. |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood.V106.11.3956.3956 |