gms | German Medical Science

59th Annual Meeting of the German Society of Neurosurgery (DGNC)
3rd Joint Meeting with the Italian Neurosurgical Society (SINch)

German Society of Neurosurgery (DGNC)

1 - 4 June 2008, Würzburg

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Preclinical evaluation of GOPI (gold-phosphole-inhibitor) for the treatment of malignant gliomas

Präklinische Evaluierung von GOPI (Gold-phosphole-inhibitor) für die Behandlung maligner Gliome

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  • corresponding author M. Farhadi - Sektion Neurochirurgische Forschung, Neurochirurgische Universitätsklinik, Heidelberg
  • R. Ahmadi - Sektion Neurochirurgische Forschung, Neurochirurgische Universitätsklinik, Heidelberg
  • J. Lohr - Sektion Neurochirurgische Forschung, Neurochirurgische Universitätsklinik, Heidelberg
  • B. Helmke - Institut für Pathologie, Universität Heidelberg
  • C. Herold-Mende - Sektion Neurochirurgische Forschung, Neurochirurgische Universitätsklinik, Heidelberg
  • A. Unterberg - Sektion Neurochirurgische Forschung, Neurochirurgische Universitätsklinik, Heidelberg

Deutsche Gesellschaft für Neurochirurgie. Società Italiana di Neurochirurgia. 59. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3. Joint Meeting mit der Italienischen Gesellschaft für Neurochirurgie (SINch). Würzburg, 01.-04.06.2008. Düsseldorf: German Medical Science GMS Publishing House; 2008. DocDI.03.06

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/dgnc2008/08dgnc163.shtml

Published: May 30, 2008

© 2008 Farhadi et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

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Objective: The flavoprotein glutathione reductase (GR) reduces NADPH-dependent glutathione disulphide (GSSG) to the sulfhydryl form GSH and is thus implicated in redox regulatory processes including redox homeostasis, detoxification of peroxides, DNA synthesis and apoptosis. Cell proliferation in neoplastic processes particularly depends on the GR system and can be suppressed by GR inhibition. In this study, the anti-tumor effect of GoPI (gold-phosphole inhibitor), a novel and highly potent inhibitor of GR has been studied in vivo.

Methods: 5 x 105 C6 glioma cells were stereotactically injected into the right striatum of 6-8 weeks old Wistar rats. Animals were treated with three repetitive intravenous applications of 22 (low dose) or 30mg/kg body weight (high dose) of GoPI (n=8) beginning nine days after tumor implantation. Control animals received intravenous injections of vehicle (500 µl DMF/Chremophor/NACl, n=4). Tumor growth was determined between day 9 and 15 by magnetic resonance imaging (MRI). Potential treatment-induced drug toxicity was evaluated by histology in normal organs of the rats. Changes in tumor cell proliferation and induction of apoptosis were assessed by Ki67 and TUNEL staining.

Results: Assessment of tumor volume by MRI demonstrated a tumor growth reduction by 56% after low dose and 86% after high dose treatment with GoPI in C6 glioma bearing rats compared to the control group. In line with this, we observed a dose-dependent decrease of tumor cell proliferation by up to 45% as determined by Ki67 labeling, while the number of apoptotic TUNEL-positive cells did not change after treatment. Finally, histological evaluation did not reveal any pathological alterations in any of the normal organs including liver, kidney, lung and heart.

Conclusions: GoPI, a novel GR inhibitor, is a highly potent anti-glioma drug. Reduced tumor growth is caused by a marked downregulation of tumor cell proliferation while induction of apoptosis is not affected. Due to its good safety profile together with its significant anti-tumor effect, our data strongly recommend further preclinical testing of GoPI in different therapeutical settings.