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

Linda Helbig, Lydia Koi, Kerstin Bruechner, Kristin Gurtner, Holger Hess-Stumpp, Kerstin Unterschemmann, Michael Baumann, Daniel Zips, Ala Yaromina*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

38 Citations (Web of Science)

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-1 alpha 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.
Original languageEnglish
Article number207
JournalRadiation Oncology
Volume9
DOIs
Publication statusPublished - 19 Sep 2014

Keywords

  • HIF pathway inhibition
  • Cisplatin
  • Fractionated radiation
  • Local tumor control
  • Tumor microenvironment
  • Human tumor xenograft

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