Molekulare Mechanismen des radiosensibilisierenden Effektes von Chloroquin beim Glioblastoma multiforme

Rübsam, Anne

dc.contributor.advisor	Giese, Alf Prof. Dr.
dc.contributor.author	Rübsam, Anne
dc.date.accessioned	2013-10-16T08:30:04Z
dc.date.available	2013-11-04T23:50:05Z
dc.date.issued	2013-10-16
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0001-BBE9-8
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-4094
dc.language.iso	deu	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subject.ddc	610	de
dc.title	Molekulare Mechanismen des radiosensibilisierenden Effektes von Chloroquin beim Glioblastoma multiforme	de
dc.type	doctoralThesis	de
dc.title.translated	Molecular mechanisms underlying radiosensitizing effects of Chloroquine in Glioma	de
dc.contributor.referee	Emmert, Steffen Prof. Dr.
dc.date.examination	2013-10-28
dc.description.abstracteng	Introduction: Glioblastoma multiforme (GBM) is the most aggressive brain malignancy. The clinical outcome remains disappointing, mainly due to inevitable GBM recurrence after postoperative radiation and chemotherapy. An enhanced DNA repair capacity has been implicated as the key component of GBM radio- and chemoresistance. Particularly, the ability of so-called brain tumour Initiating stem-like cells (BTICs) to efficiently repair DNA damage induced by radiotherapy is the key molecular mechanism involved in the post-therapy GBM recurrence. Interference with DNA repair capacity has emerged as an important strategy in combination therapy for GBM. DNA intercalating agent chloroquine (ClQ) exerts cytotoxic effects in different types of cancer cells including glioma. Among the versatile mechanisms underlying ClQ-mediated cytotoxicity, interference with DNA repair has been implicated. Our aim was to investigate the effect of CIQ on DNA repair capacity in BTICs. Methods: BTIC-like population selected from glioma line G112 was treated with ionizing radiation (IR) in the absense or presence of ClQ. Cell growth rate was evaluated by using growth curve analysis. DNA repair capacity was evaluated by using the reporter assay or assessing the IR-induced phosphorylation of H2AX, a marker for DNA double-strand breaks (DSBs).Results: Treatment with ClQ within a concentration range of 10 µg/ml to 20µg/ml inhibits BTICs growth in vitro. The effective dose of IR treatment for BTICs lies within the range of 5Gy to 10Gy. The combination of sub-effective doses of ClQ (2,5 µg/ml) and IR (2,5Gy) has a synergistic effect on the growth of BTICs compared to single treatments. We found that IR-induced H2AX phosphorylation is significantly decreased in the presense of ClQ. These results indicate that ClQ impairs an assembly of DNA damage foci at DSBs induced by IR. Conclusions: The data from our study suggests that impairment of DNA repair in response to IR is an important mechanism of radiosensitization of BTIC by ClQ.	de
dc.contributor.coReferee	Mausberg, Rainer Prof. Dr.
dc.subject.ger	Glioblastoma multiforme	de
dc.subject.ger	Tumorstammzellen	de
dc.subject.ger	Chloroquin	de
dc.subject.ger	DNA-Reparatur	de
dc.subject.ger	Radioresistenz	de
dc.subject.eng	glioma	de
dc.subject.eng	brain tumour initiation stem-like cells	de
dc.subject.eng	radioresistance	de
dc.subject.eng	chloroquine	de
dc.subject.eng	DNA repair	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0001-BBE9-8-8
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	Neurochirurgie (PPN619876271)	de
dc.description.embargoed	2013-11-04
dc.identifier.ppn	770070868

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