title: SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model.
abstract: OBJECTIVE
  Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the mesothelium with high chemotherapeutic resistance. In this study, the preclinical therapeutic activity of the multiple tyrosine kinase inhibitor, SU6668, against MPM was examined.
  
  
  METHODS
  Two human MPM cell lines with different pro-angiogenic cytokine expression, Y-MESO-14 cells that express high levels of vascular endothelial growth factor (VEGF) and MSTO-211H cells that express high levels of basic fibroblast growth factor (bFGF), were orthotopically inoculated into the thoracic cavities of mice with severe combined immunodeficiency. The mice with MPM were treated or not treated with SU6668 (200 mg/kg/day).
  
  
  RESULTS
  SU6668 abrogated the proliferation of endothelial cells stimulated by VEGF or bFGF, but did not directly affect the growth of human MPM cells in vitro. In this orthotopic implantation model, treatment with SU6668 effectively reduced tumour weight and pleural effusion volumes, in association with inhibition of the growth of tumour vasculature. More importantly, treatment with SU6668 significantly prolonged survival time in mice with MPM.
  
  
  CONCLUSIONS
  These findings suggest that SU6668 has a promising therapeutic effect on the progression of MPM in vivo through its anti-angiogenic effects.
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Trung The
authors.initials: TT
authors.lastname: Van
authors.forename: Masaki
authors.initials: M
authors.lastname: Hanibuchi
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Goto
authors.forename: Takuya
authors.initials: T
authors.lastname: Kuramoto
authors.forename: Sawaka
authors.initials: S
authors.lastname: Yukishige
authors.forename: Soji
authors.initials: S
authors.lastname: Kakiuchi
authors.forename: Seidai
authors.initials: S
authors.lastname: Sato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Le Tan
authors.initials: le T
authors.lastname: Dat
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Akiyama
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000078183:Oxindoles; D016066:Pleural Effusion, Malignant / Q000188:drug therapy; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011422:Propionates; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C412603:orantinib