[HTML][HTML] BAY 87–2243, a novel inhibitor of hypoxia-induced gene activation, improves local tumor control after fractionated irradiation in a schedule-dependent …
L Helbig, L Koi, K Brüchner, K Gurtner… - Radiation …, 2014 - Springer
L Helbig, L Koi, K Brüchner, K Gurtner, H Hess-Stumpp, K Unterschemmann, M Baumann…
Radiation oncology, 2014•SpringerBackground 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 …
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 …
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.
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