title: BAY 87-2243, a novel inhibitor of hypoxia-induced gene activation, improves local tumor control after fractionated irradiation in a schedule-dependent manner in head and neck human xenografts.
abstract: BACKGROUND
  The transcription factor hypoxia-inducible factor-1 (HIF-1) pathway plays an important role in tumor response to cytotoxic treatments. We investigated the effects of a novel small molecule inhibitor of mitochondrial complex I and hypoxia-induced HIF-1 activity BAY-87-2243, on tumor microenvironment and response of human squamous cell carcinoma (hSCC) to clinically relevant fractionated radiotherapy (RT) with and without concomitant chemotherapy.
  
  
  METHODS
  When UT-SCC-5 hSCC xenografts in nude mice reached 6 mm in diameter BAY-87-2243 or carrier was administered before and/or during RT or radiochemotherapy with concomitant cisplatin (RCT). Local tumor control was evaluated 150 days after irradiation and the doses to control 50% of tumors (TCD50) were compared between treatment arms. Tumors were excised at different time points during BAY-87-2243 or carrier treatment for western blot and immunohistological investigations.
  
  
  RESULTS
  BAY-87-2243 markedly decreased nuclear HIF-1α expression and pimonidazole hypoxic fraction already after 3 days of drug treatment. BAY-87-2243 prior to RT significantly reduced TCD50 from 123 to 100 Gy (p=0.037). Additional BAY-87-2243 application during RT did not decrease TCD50. BAY-87-2243 before and during radiochemotherapy did not improve local tumor control.
  
  
  CONCLUSIONS
  Pronounced reduction of tumor hypoxia by application of BAY-87-2243 prior to RT improved local tumor control. The results demonstrate that radiosensitizing effect importantly depends on treatment schedule. The data support further investigations of HIF-1 pathway inhibitors for radiotherapy and of predictive tests to select patients who will benefit from this combined treatment.
authors.forename: Linda
authors.initials: L
authors.lastname: Helbig
authors.forename: Lydia
authors.initials: L
authors.lastname: Koi
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brüchner
authors.forename: Kristin
authors.initials: K
authors.lastname: Gurtner
authors.forename: Holger
authors.initials: H
authors.lastname: Hess-Stumpp
authors.forename: Kerstin
authors.initials: K
authors.lastname: Unterschemmann
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany. ala.yaromina@maastrichtuniversity.nl.
authors.forename: Ala
authors.initials: A
authors.lastname: Yaromina
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D059248:Chemoradiotherapy / Q000379:methods; D019583:Dose Fractionation, Radiation; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D010069:Oxadiazoles / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: C000591541:1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010069:Oxadiazoles; D011720:Pyrazoles; D011838:Radiation-Sensitizing Agents