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Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation

Klein, Carmen ; Dokic, Ivana ; Mairani, Andrea ; Mein, Stewart ; Brons, Stephan ; Häring, Peter ; Haberer, Thomas ; Jäkel, Oliver ; Zimmermann, Astrid ; Zenke, Frank ; Blaukat, Andree ; Debus, Jürgen ; Abdollahi, Amir

In: Radiation Oncology, 12 (2017), Nr. 208. pp. 1-8. ISSN 1748-717X

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Download (1MB) | Lizenz: Creative Commons LizenzvertragOvercoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation by Klein, Carmen ; Dokic, Ivana ; Mairani, Andrea ; Mein, Stewart ; Brons, Stephan ; Häring, Peter ; Haberer, Thomas ; Jäkel, Oliver ; Zimmermann, Astrid ; Zenke, Frank ; Blaukat, Andree ; Debus, Jürgen ; Abdollahi, Amir underlies the terms of Creative Commons Attribution 4.0

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Abstract

Background: Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibitors of DNA-Damage Response (DDR) on tumor cell radiosensitivity under hypoxic conditions.

Methods: Human non-small cell lung cancer (NSCLC) models, A549 and H1437, were irradiated with dose series of photon and carbon ions under hypoxia (1% O2) vs. normoxic conditions (21% O2). Clonogenic survival was studied after dual combinations of radiotherapy with inhibitors of DNA-dependent Protein Kinase (DNAPKi, M3814) and ATM serine/threonine kinase (ATMi).

Results: The OER at 30% survival for photon irradiation of A549 cells was 1.4. The maximal oxygen effect measured as survival ratio was 2.34 at 8 Gy photon irradiation of A549 cells. In contrast, no significant oxygen effect was found after carbon ion irradiation. Accordingly, the relative effect of 6 Gy carbon ions was determined as 3.8 under normoxia and. 4.11 under hypoxia. ATM and DNA-PK inhibitors dose dependently sensitized tumor cells for both radiation qualities. For 100 nM DNAPKi the survival ratio at 4 Gy more than doubled from 1.59 under normoxia to 3.3 under hypoxia revealing a strong radiosensitizing effect under hypoxic conditions. In contrast, this ratio only moderately increased after photon irradiation and ATMi under hypoxia. The most effective treatment was combined carbon ion irradiation and DNA damage repair inhibition.

Conclusions: Carbon ions efficiently eradicate hypoxic tumor cells. Both, ATMi and DNAPKi elicit radiosensitizing effects. DNAPKi preferentially sensitizes hypoxic cells to radiotherapy.

Item Type: Article
Journal or Publication Title: Radiation Oncology
Volume: 12
Number: 208
Publisher: BioMed Central
Place of Publication: London
Date Deposited: 27 Apr 2018 12:35
Date: 2017
ISSN: 1748-717X
Page Range: pp. 1-8
Faculties / Institutes: Service facilities > German Cancer Research Center (DKFZ)
Medizinische Fakultät Heidelberg > Radiologische Universitätsklinik
Medizinische Fakultät Heidelberg > Heidelberg Ion-Beam Therapy Center (HIT)
Subjects: 610 Medical sciences Medicine
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