title: TSU68, an antiangiogenic receptor tyrosine kinase inhibitor, induces tumor vascular normalization in a human cancer xenograft nude mouse model.
abstract: OBJECTIVE
  Combination therapy using antiangiogenic and cytotoxic agents is a useful strategy for advanced cancer, but the mechanism has not yet been elucidated. Moreover, there is a persistent paradox that destroying tumor vasculature with antiangiogenic agents disturbs the delivery of cytotoxic agents. It has been hypothesized that antiangiogenic agents can lead to normalization of tumor vessels that are structurally and functionally abnormal. The normalization means enhancing the deliver of cytotoxic agents. Our purpose was to investigate whether TSU68, a multiple receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), would induce the normalization of tumor vessels.
  
  
  METHODS
  TSU68 was administered for 7 days to mice with xenografted tumors. Tumors of interstitial fluid pressure (IFP) were measured before and after administration of agents. Immunofluorescence double staining for CD31 and alpha-SMA was performed, and a medical video endoscopy system with narrowband illumination (NBI) was used to visualize the vascular pattern.
  
  
  RESULTS
  TSU68 treatment decreased IFP significantly. Immunofluorescence double staining showed a significant increase in the fraction of pericyte coverage in the TSU68-treated group. NBI endoscopy showed that many tumor vessels in TSU68-treated mice were pruned and the diameters of remaining vessels were reduced.
  
  
  CONCLUSIONS
  The data supported our hypothesis of tumor vascular normalization by the antiangiogenic agent TSU68.
authors.affiliation: Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3125, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Ohta
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kawabata
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hiramatsu
authors.forename: Kinji
authors.initials: K
authors.lastname: Kamiya
authors.forename: Megumi
authors.initials: M
authors.lastname: Baba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konno
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D003106:Colon / Q000098:blood supply* / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D000078183:Oxindoles; D011422:Propionates / Q000494:pharmacology*; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism; D012680:Sensitivity and Specificity; D014183:Transplantation, Heterologous; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; C412603:orantinib; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2