TY  - JOUR
PB  - BioMed Central
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/24322/
EP  - 8
VL  - 12
TI  - Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation
JF  - Radiation Oncology
IS  - 208
Y1  - 2017///
A1  - Klein, Carmen
A1  - Dokic, Ivana
A1  - Mairani, Andrea
A1  - Mein, Stewart
A1  - Brons, Stephan
A1  - Häring, Peter
A1  - Haberer, Thomas
A1  - Jäkel, Oliver
A1  - Zimmermann, Astrid
A1  - Zenke, Frank
A1  - Blaukat, Andree
A1  - Debus, Jürgen
A1  - Abdollahi, Amir
N2  - 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.
CY  - London
SP  - 1
SN  - 1748-717X
AV  - public
ID  - heidok24322
ER  -