title: Vascular-targeted agents for the treatment of angiosarcoma.
abstract: OBJECTIVE
  Angiosarcomas are rare, aggressive vascular tumours known to express vascular endothelial growth factor (VEGF), a key pro-angiogenic growth factor. The aim of this study was to determine the potential effects of vascular-targeted agents for the treatment of angiosarcoma, using two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS), and human dermal microvascular endothelial cells (HuDMECs) for comparison.
  
  
  METHODS
  Protein arrays were used to assess the expression of angiogenesis-related proteins, and potential drug targets were assessed by ELISA and Western blotting. Response to vascular-targeted agents, including bevacizumab an anti-VEGF antibody, axitinib a VEGF-receptor tyrosine kinase inhibitor, everolimus an mTOR inhibitor, selumetinib a MEK inhibitor and vadimezan a vascular-disrupting agent were compared in functional in vitro cellular assays, including viability, differentiation and migration assays.
  
  
  RESULTS
  ASM and ISO-HAS cells expressed a broad range of pro-angiogenic growth factors. ASM and ISO-HAS VEGF expression was significantly increased (p = 0.029) compared with HuDMECs. Striking responses were seen to vadimezan with an IC50 of 90 and 150 μg/ml for ASM and ISO-HAS cells, respectively. Selumetinib inhibited ASM with an IC50 of 1,750 ng/ml, but was not effective in ISO-HAS. Everolimus reduced both ASM and ISO-HAS viable cell counts by 20 % (p < 0.001). Minimal responses were observed to bevacizumab and axitinib in assays with ASM and ISO-HAS cells.
  
  
  CONCLUSIONS
  Further studies are warranted to investigate mTOR inhibitors, MEK inhibitors and vascular-disrupting agents for the treatment of angiosarcoma.
authors.affiliation: Microcirculation Research Group, Academic Unit of Surgical Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, S10 2RX, UK, r.j.young@sheffield.ac.uk.
authors.forename: R J
authors.initials: RJ
authors.lastname: Young
authors.forename: P J
authors.initials: PJ
authors.lastname: Woll
authors.forename: C A
authors.initials: CA
authors.lastname: Staton
authors.forename: M W R
authors.initials: MW
authors.lastname: Reed
authors.forename: N J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000077784:Axitinib; D000068258:Bevacizumab; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D000068338:Everolimus; D006394:Hemangiosarcoma / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D040081:Protein Array Analysis; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D007093:Imidazoles; D007191:Indazoles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D004317:Doxorubicin; D000068338:Everolimus; D000077784:Axitinib; D017239:Paclitaxel; D020123:Sirolimus