Koehl, Gudrun E. and Geissler, Edward K. and lacobelli, Massimo and Frei, Caroline and Burger, Verena and Haffner, Silvia and Holler, Ernst and Andreesen, Reinhard and Schlitt, Hans J. and Eissner, Guenther (2007) An endothelium protecting and stabilizing drug, has an anti-angiogenic potential in vitro and in vivo. CANCER BIOLOGY & THERAPY, 6 (5). pp. 686-690. ISSN 1538-4047,
Full text not available from this repository. (Request a copy)Abstract
Defibrotide (DF) is a polydisperse mixture of 90% single-stranded oligonucleotides with anti-thrombotic and anti-apoptotic functions. DF is used in the treatment of endothelial complications in the course of allogeneic stem cell transplantation. Recent preclinical evidence suggests that DF might also have anti-neoplastic properties. In the present study we hypothesized that DF might inhibit tumors via an anti-angiogenic effect. The anti-angiogenic potential of DF was tested in vitro using human microvascular endothelial cells forming vessel structures across a layer of dermal fibroblasts. Our results show that pharmacologic DF concentrations (100 mu g/ml) significantly reduced vessel formation in this assay. Similarly, DF blocked sprouting from cultured rat aortic rings. In vivo, angiogenesis in a human gastric tumor (TMK1) implanted in dorsal skin-fold chambers (in nude mice) was inhibited by i.v. application of 450 mg/kg DF. Notably, due to its short half-life, DF was most effective when given on a daily basis. Although the precise mechanism of DF remains to be elucidated, initial Western blots 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. However, in vitro data suggest that DF acts independently of vascular endothelial growth factor. Taken together, our data suggest that while DF is known for its endothelium-protecting function in SCT, it also inhibits formation of new blood vessels, and thus should be considered for further testing as an adjuvant anti-cancer agent, either alone, or in combination with other drugs.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SEVERE VENOOCCLUSIVE DISEASE; HIGH-RISK POPULATION; P70 S6 KINASE; SIGNIFICANT TOXICITY; DEFIBROTIDE; CELLS; CANCER; ALLOGENICITY; ACTIVATION; GROWTH; defibrotide; angiogenesis; endothelium; tumor |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Dec 2020 10:55 |
| Last Modified: | 10 Dec 2020 10:55 |
| URI: | https://pred.uni-regensburg.de/id/eprint/32789 |
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