Defibrotide: an endothelium protecting and stabilizing drug, has an anti-angiogenic potential in vitro and in vivo.
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 mug/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.
Koehl
Gudrun E
GE
Department of Surgery, Regensburg University Medical Center, Regensburg, Germany.
Geissler
Edward K
EK
Iacobelli
Massimo
M
Frei
Caroline
C
Burger
Verena
V
Haffner
Silvia
S
Holler
Ernst
E
Andreesen
Reinhard
R
Schlitt
Hans J
HJ
Eissner
Günther
G
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000502:physiology; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D001681:Biological Assay; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D052157:Aptamers, Nucleotide; D004338:Drug Combinations; D007797:Laminin; D010975:Platelet Aggregation Inhibitors; D011089:Polydeoxyribonucleotides; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; C036901:defibrotide; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa