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
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
Helbig, L.; Koi, L.; Bruechner, K.; Gurtner, K.; Hess-Stumpp, H.; Unterschemmann, K.; Baumann, M.; Zips, D.; Yaromina, A.
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.
Keywords: HIF pathway inhibition; Cisplatin; Fractionated radiation; Local tumor control; Tumor microenvironment; Human tumor xenograft
-
Radiation Oncology 19(2014)9, 207
DOI: 10.1186/1748-717X-9-207
Cited 47 times in Scopus
Permalink: https://www.hzdr.de/publications/Publ-21026