title: Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas.
abstract: BACKGROUND
  Human sarcomas with a poor response to vascular endothelial growth factor-A (VEGF-A) inhibition and radiation therapy (RT) have upregulation of hypoxia-inducible factor 1α (HIF-1α) and HIF-1α target genes. This study examines the addition of the hypoxia-activated chemotherapy TH-302 to VEGF-A inhibition and RT (a.k.a. trimodality therapy).
  
  
  METHODS
  Trimodality therapy was examined in two xenograft models and in vitro in tumour endothelial cells and sarcoma cell lines.
  
  
  RESULTS
  In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth. When TH-302 was added, this trimodality therapy completely blocked tumour growth with tumours remaining dormant for over 3 months after cessation of therapy. Trimodality therapy caused 2.6- to 6.2-fold more endothelial cell-specific apoptosis than bimodality therapies, and microvessel density and HIF-1α activity were reduced to 11-13% and 13-20% of control, respectively. When trimodality therapy was examined in vitro, increases in DNA damage and apoptosis were much more pronounced in tumour endothelial cells compared with that in sarcoma cells, especially under hypoxia.
  
  
  CONCLUSIONS
  The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1α activity.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, H-1209, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: C
authors.initials: C
authors.lastname: Yoon
authors.affiliation: 1] Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA [2] Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: 1] Department of Surgery, Memorial Sloan-Kettering Cancer Center, H-1209, 1275 York Avenue, New York, NY 10021, USA [2] Department of Surgery, Seoul National University Bundang Hospital, Sungnam, South Korea.
authors.forename: D J
authors.initials: DJ
authors.lastname: Park
authors.affiliation: 1] Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA [2] Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: W D
authors.initials: WD
authors.lastname: Tap
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: T S K
authors.initials: TS
authors.lastname: Eisinger-Mathason
authors.affiliation: Threshold Pharmaceuticals, South San Francisco, CA 94080, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Hart
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: E
authors.initials: E
authors.lastname: Choy
authors.affiliation: 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA [2] Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Simon
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, H-1209, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Yoon
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010752:Phosphoramide Mustards / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy* / Q000532:radiotherapy*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; C552526:TH 302; D042461:Vascular Endothelial Growth Factor A