title: Hypoxia-inducible factor pathway inhibition resolves tumor hypoxia and improves local tumor control after single-dose irradiation.
abstract: OBJECTIVE
  To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors.
  
  
  METHODS
  UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD50) was calculated.
  
  
  RESULTS
  BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P<.0001) and in UT-SCC-14 (0.3% vs 19%, P<.0001). This decrease was accompanied by a significant increase in fraction of perfused vessels in UT-SCC-14 but not in UT-SCC-5. Bromodeoxyuridine and Ki67 labeling indices were significantly reduced only in UT-SCC-5. No significant changes were observed in vascular area or necrosis. BAY-84-7296 before single-dose irradiation significantly decreased TCD50, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD50.
  
  
  CONCLUSIONS
  BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of radiation response. Whether this mechanism contributes to the improved outcome of fractionated chemoradiation therapy warrants further investigation.
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: Linda
authors: L
authors: Helbig
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Deutsches Konsortium für Translationale Krebsforschung, Site Dresden, Dresden, Germany.
authors: Lydia
authors: L
authors: Koi
authors: Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Institute of Radiooncology Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors: Kerstin
authors: K
authors: Brüchner
authors: Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: Kristin
authors: K
authors: Gurtner
authors: Global Drug Discovery, Bayer Pharma, Berlin, Germany.
authors: Holger
authors: H
authors: Hess-Stumpp
authors: Global Drug Discovery, Bayer Pharma, Berlin, Germany.
authors: Kerstin
authors: K
authors: Unterschemmann
authors: Radiation Oncology, University of Zurich, Zurich, Switzerland.
authors: Martin
authors: M
authors: Pruschy
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Deutsches Konsortium für Translationale Krebsforschung, Site Dresden, Dresden, Germany; Institute of Radiooncology Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors: Michael
authors: M
authors: Baumann
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Radiation Oncology (MAASTRO Laboratory), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address: ala.yaromina@tu-dresden.de.
authors: Ala
authors: A
authors: Yaromina
authors: Radiation Oncology, Eberhard Karls University Tübingen, Tübingen, Germany; Deutsches Konsortium für Translationale Krebsforschung, Site Tübingen, Tübingen, Germany.
authors: Daniel
authors: D
authors: Zips
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects* / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D005260:Female; D064593:Heterografts; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods; D009593:Nitroimidazoles / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects* / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D011897:Random Allocation; D059016:Tumor Microenvironment
chemical_list: D000588:Amines; C586268:BAY-84-7296; D051793:Hypoxia-Inducible Factor 1; D019394:Ki-67 Antigen; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C033815:pimonidazole; D042967:Electron Transport Complex I; D001973:Bromodeoxyuridine