title: Novel tubulin antagonist pretubulysin displays antivascular properties in vitro and in vivo.
abstract: OBJECTIVE
  Pretubulysin (PT) is a novel, synthetically accessible myxobacterial compound that acts as a tubulin-depolymerizing agent and inhibits cancer cell growth in vitro and in vivo. Moreover, PT was found to attenuate tumor angiogenesis. Here, we hypothesized that PT could exert antivascular activities on existing tumor vessels.
  
  
  RESULTS
  We aimed to characterize the antivascular effects of PT and to elucidate the underlying mechanisms in endothelial cells. In vitro, PT rapidly induced endothelial hyperpermeability and a concentration-dependent disassembly of established endothelial tubes on Matrigel and in an ex vivo aortic ring model. It disrupted endothelial cell junctions and triggered F-actin stress fiber formation and cell contraction by the RhoA/Rho-associated protein kinase pathway without causing cell death. In vivo, using a hamster dorsal skinfold chamber preparation, PT significantly decreased blood flow and vessel diameter in hamster A-Mel-3 amelanotic melanoma tumors but not in the neighboring healthy tissue. In a second tumor model using mice with subcutaneous murine B16 melanoma tumors, a single dose of PT (10 mg/kg) caused a shut down of tumor blood flow and a strong central tumor cell necrosis within 24 hours. Repeated PT administration significantly decelerates tumor growth and seems to be well tolerated.
  
  
  CONCLUSIONS
  In summary, we could show for the first time that the antitumor effect of PT is, at least in part, mediated via its antivascular activities on existing tumor vessels.
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology (V.K.K., S.Z., A.M.V.) and Walter-Brendel-Center for Experimental Medicine (D.G.), University of Munich, Munich, Germany; Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany (A.U., U.K.); and Institute of Pharmaceutical Biology, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany (V.K.K., R.F.).
authors.forename: Verena K
authors.initials: VK
authors.lastname: Kretzschmann
authors.forename: Donata
authors.initials: D
authors.lastname: Gellrich
authors.forename: Angelika
authors.initials: A
authors.lastname: Ullrich
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Uli
authors.initials: U
authors.lastname: Kazmaier
authors.forename: Robert
authors.initials: R
authors.lastname: Fürst
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D009336:Necrosis; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000187:drug effects; D012983:Soft Tissue Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D009842:Oligopeptides; D014404:Tubulin; D050257:Tubulin Modulators; D000205:Actomyosin; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D020742:rhoA GTP-Binding Protein; C575012:pretubulysin
keywords: drug research; endothelial cells; neoplasms; pharmacology