title: Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma.
abstract: OBJECTIVE
  Cholangiocarcinoma is a refractory cancer whose incidence has been increasing worldwide in recent years. Neoangiogenesis plays an important role in the growth of various solid cancers, including cholangiocarcinoma. Vascular endothelial growth factor plays an important role in tumor-induced angiogenesis and its expression is associated with the progression and prognosis of cholangiocarcinoma. This study examined whether axitinib (AG-013736, INLYTA(®)), a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, could be a potentially useful therapeutic agent for cholangiocarcinoma.
  
  
  METHODS
  We performed expression profiling of angiogenesis-related molecules in eight cholangiocarcinoma cell lines and found that three of them showed high vascular endothelial growth factor expression. Among them, we examined the in vivo anti-tumor effect of axitinib on NCC-BD1 (a gemcitabine-sensitive extra-hepatic cholangiocarcinoma cell line) and TKKK (a gemcitabine-resistant intra-hepatic cholangiocarcinoma cell line) using subcutaneous xenograft models.
  
  
  RESULTS
  Oral administration of axitinib significantly inhibited the growth of TKKK xenografts at a dose of 6 mg kg(-1) day(-1) (P<0.05), and the growth of NCC-BD1 xenografts at 30 mg kg(-1)day(-1) (P<0.05). Treated tumors showed a significant decrease of microvessel density and the tumor cell proliferation index and a mild but significant increase of the apoptotic index in comparison with untreated tumors.
  
  
  CONCLUSIONS
  Our results suggest that axitinib should be a promising therapy for vascular endothelial growth factor-expressing cholangiocarcinoma, irrespective of tumor origin and gemcitabine sensitivity.
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ojima
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
authors.affiliation: Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Furukawa
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo tashibat@ncc.go.jp.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000077784:Axitinib; D001650:Bile Duct Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000098:blood supply / Q000188:drug therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000077784:Axitinib; D000093542:Gemcitabine
keywords: VEGFR-TKI; axitinib; cholangiocarcinoma; xenograft model