gms | German Medical Science

61st Annual Meeting of the German Society of Neurosurgery (DGNC) as part of the Neurowoche 2010
Joint Meeting with the Brazilian Society of Neurosurgery on the 20 September 2010

German Society of Neurosurgery (DGNC)

21 - 25 September 2010, Mannheim

Chloroquine sensitizes experimental gliomas derived from brain tumor initiating stem-like cells to radiation therapy

Meeting Abstract

  • Alf Giese - Klinik für Neurochirurgie, Universitätsmedizin Göttingen, Deutschland
  • Julia Pruefer - Klinik für Neurochirurgie, Universitätsmedizin Göttingen, Deutschland
  • Veit Rohde - Klinik für Neurochirurgie, Universitätsmedizin Göttingen, Deutschland
  • Margret Rave-Fraenk - Klinik für Strahlentherapie und Radioonkologie, Universitätsmedizin Göttingen, Deutschland
  • Walter Schulz-Schaeffer - Institut für Neuropathologie, Universitätsmedizin Göttingen, Deutschland
  • Ella Kim - Klinik für Neurochirurgie, Universitätsmedizin Göttingen, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 61. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC) im Rahmen der Neurowoche 2010. Mannheim, 21.-25.09.2010. Düsseldorf: German Medical Science GMS Publishing House; 2010. DocV1545

DOI: 10.3205/10dgnc022, URN: urn:nbn:de:0183-10dgnc0227

Published: September 16, 2010

© 2010 Giese et al.
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Outline

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Objective: The survival of patients with glioblastoma remains low because of resistance of glioma cells to radiation and chemotherapy. Brain Tumour Initiating Cells (BTICs) have been implicated in the posttherapy recurrence of gliomas. The antimalaria and antirheumatic drug chloroquine (ClQ) has recently emerged as a potential anti-cancer agent. We have previously shown that ClQ activates the apoptotic response in glioma cells through activation of the p53 tumour suppressor pathway. However, the p53 pathway is frequently impaired in gliomas. The purpose of this study was to explore the cytotoxic and potentially radiation sensitizing effects of ClQ in BTICs with mutant p53.

Methods: BTICs were selected from primary GBM cultures or the glioma cell line G112 and propagated in serum-free conditions. The tumorigenic potential and therapeutic responses of BTICs were evaluated in an orthotopic glioma mouse model using time to neurological deterioration as an endpoint. Systemic treatment of nude mice bearing experimental BTIC derived tumors was performed by intraperitoneal injections of ClQ. Radiation treatment consisted of six 2,5 Gy fractions applied on six consecutive days starting at five weeks after intracranial implantation of BTICs.

Results: Experimental tumours formed by BTICs with mutant p53 (BTIC-mutp53) showed no response to treatments of fractionated radiation (6x2,5 Gy, total dose 15 Gy), a dose effective in treatment of non-BTIC experimental tumors. Neither systemic treatment with ClQ alone showed a significant therapeutic effect. However, the combined treatment with ClQ and radiation (ClQ+IR) showed a significant (n=36 tumors, p<0,0007) delay in tumour progression. An average survival time for untreated, IR-, ClQ- or ClQ+IR treated groups was 114±18 (n=10), 119±25 (n=11), 96±20 (n=7) and 147±25 days (n=8), respectively. Immunohistochemical assessments showed a considerably higher apoptotic indices in tumours treated with ClQ+IR compared to tumours treated with ClQ or IR alone or untreated tumours.

Conclusions: ClQ exerts radiosensitizing effects on BTICs expressing mutant p53. Modulation of apoptosis is one of the mechanism(s) underlying ClQ-mediated radiosensitization. ClQ possesses a therapeutic potential in the treatment of the BTIC component of malignant gliomas and can be serve as an adjunct to radiotherapy of gliomas.