eprintid: 24322
rev_number: 13
eprint_status: archive
userid: 1589
dir: disk0/00/02/43/22
datestamp: 2018-04-27 12:35:24
lastmod: 2024-04-19 10:34:29
status_changed: 2018-04-27 12:35:24
type: article
metadata_visibility: show
creators_name: Klein, Carmen
creators_name: Dokic, Ivana
creators_name: Mairani, Andrea
creators_name: Mein, Stewart
creators_name: Brons, Stephan
creators_name: Häring, Peter
creators_name: Haberer, Thomas
creators_name: Jäkel, Oliver
creators_name: Zimmermann, Astrid
creators_name: Zenke, Frank
creators_name: Blaukat, Andree
creators_name: Debus, Jürgen
creators_name: Abdollahi, Amir
title: Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation
subjects: 610
divisions: 850300
divisions: 911400
divisions: 950400
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.
date: 2017
publisher: BioMed Central
id_scheme: DOI
ppn_swb: 1655278584
own_urn: urn:nbn:de:bsz:16-heidok-243224
language: eng
bibsort: KLEINCARMEOVERCOMING2017
full_text_status: public
publication: Radiation Oncology
volume: 12
number: 208
place_of_pub: London
pagerange: 1-8
issn: 1748-717X
citation:   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  (2017) Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation.  Radiation Oncology, 12 (208).  pp. 1-8.  ISSN 1748-717X     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/24322/1/13014_2017_Article_939.pdf