PMID- 25234922
OWN - NLM
STAT- MEDLINE
DCOM- 20150511
LR  - 20211021
IS  - 1748-717X (Electronic)
IS  - 1748-717X (Linking)
VI  - 9
DP  - 2014 Sep 19
TI  - 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.
PG  - 207
LID - 10.1186/1748-717X-9-207 [doi]
LID - 207
AB  - 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-1alpha 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.
FAU - Helbig, Linda
AU  - Helbig L
FAU - Koi, Lydia
AU  - Koi L
FAU - Bruchner, Kerstin
AU  - Bruchner K
FAU - Gurtner, Kristin
AU  - Gurtner K
FAU - Hess-Stumpp, Holger
AU  - Hess-Stumpp H
FAU - Unterschemmann, Kerstin
AU  - Unterschemmann K
FAU - Baumann, Michael
AU  - Baumann M
FAU - Zips, Daniel
AU  - Zips D
FAU - Yaromina, Ala
AU  - Yaromina A
AD  - OncoRay - National Center for Radiation Research in Oncology, Medical Faculty 
      Carl Gustav Carus, TU Dresden, Dresden, Germany. 
      ala.yaromina@maastrichtuniversity.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140919
PL  - England
TA  - Radiat Oncol
JT  - Radiation oncology (London, England)
JID - 101265111
RN  - 0 
      (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)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Oxadiazoles)
RN  - 0 (Pyrazoles)
RN  - 0 (Radiation-Sensitizing Agents)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Blotting, Western
MH  - Carcinoma, Squamous Cell/*pathology
MH  - Cell Hypoxia/drug effects
MH  - Chemoradiotherapy/methods
MH  - Dose Fractionation, Radiation
MH  - Head and Neck Neoplasms/*pathology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors
MH  - Mice
MH  - Mice, Nude
MH  - Oxadiazoles/*pharmacology
MH  - Pyrazoles/*pharmacology
MH  - Radiation-Sensitizing Agents/*pharmacology
MH  - Squamous Cell Carcinoma of Head and Neck
MH  - Xenograft Model Antitumor Assays
PMC - PMC4262387
EDAT- 2014/09/23 06:00
MHDA- 2015/05/12 06:00
PMCR- 2014/09/19
CRDT- 2014/09/20 06:00
PHST- 2014/07/01 00:00 [received]
PHST- 2014/09/09 00:00 [accepted]
PHST- 2014/09/20 06:00 [entrez]
PHST- 2014/09/23 06:00 [pubmed]
PHST- 2015/05/12 06:00 [medline]
PHST- 2014/09/19 00:00 [pmc-release]
AID - 1748-717X-9-207 [pii]
AID - 1174 [pii]
AID - 10.1186/1748-717X-9-207 [doi]
PST - epublish
SO  - Radiat Oncol. 2014 Sep 19;9:207. doi: 10.1186/1748-717X-9-207.