gms | German Medical Science

55. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e. V. (DGNC)
1. Joint Meeting mit der Ungarischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

25. bis 28.04.2004, Köln

Local intracerebral treatment with a thromboxane synthase inhibitor enhances the efficiency of conventional chemotherapy in a human glioblastoma xenograft model

Die lokale intrazerebrale Behandlung mit einem Thromboxansynthase-Inhibitor verstärkt die Effizienz konventioneller Chemotherapie in einem experimentellen Glioblastom-Modell

Meeting Abstract

  • corresponding author Nils Ole Schmidt - Neurosurgical Oncology Laboratory, Brigham & Women's Hospital / Harvard Medical School, Boston /USA; Klinik für Neurochirurgie, Universitätsklinikum HH-Eppendorf, Hamburg
  • A. Giese - Klinik für Neurochirurgie, Universitätsklinikum HH-Eppendorf, Hamburg; Klinik für Neurochirurgie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck
  • M. Westphal - Klinik für Neurochirurgie, Universitätsklinikum HH-Eppendorf, Hamburg
  • P. M. Black - Neurosurgical Oncology Laboratory, Brigham & Women's Hospital / Harvard Medical School, Boston /USA
  • R. S. Carroll - Neurosurgical Oncology Laboratory, Brigham & Women's Hospital / Harvard Medical School, Boston /USA

Deutsche Gesellschaft für Neurochirurgie. Ungarische Gesellschaft für Neurochirurgie. 55. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 1. Joint Meeting mit der Ungarischen Gesellschaft für Neurochirurgie. Köln, 25.-28.04.2004. Düsseldorf, Köln: German Medical Science; 2004. DocP 06.61

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgnc2004/04dgnc0344.shtml

Veröffentlicht: 23. April 2004

© 2004 Schmidt et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Objective

Thromboxane synthase (TXSA), an enzyme of the arachidonic acid metabolism, is upregulated in human glial tumors and involved in the regulation of glioma cell invasion, which is one of the major limiting factors of current therapeutic strategies in this disease. Recent in vitro studies indicate that the inhibition of thromboxane synthase activity at non-cytotoxic concentrations blocks the invasive phenotype of glioma cells. This in turn increases a pro-apoptotic disposition, and therefore the susceptibility to standard apoptosis inducing chemotherapeutic compounds like BCNU, camptothecin and etoposide.

Results

Here, we evaluated the therapeutic in vivo effects of furegrelate, a clinically tested TXSA inhibitor, in orthotopic U87 human glioblastoma xenografts by using local intracerebral microinfusions at 0.5 and 2 mg/kg/d. Local delivery of furegrelate by osmotic mini-pumps at 2 mg/kg/d for 21 days significantly inhibited the growth of well-established orthotopic gliomas in a nude mice model (76.12%, p<0.05). Histological analysis of the tumors indicated that the anti-tumor effects were mediated by a significant reduction of the proliferation rate (24.14%, p<0.01), of the intratumoral microvessel density (30.42%, p<0.05) and a significant increase of tumor cell apoptosis (2.9 fold, p>0.005). Furegrelate and BCNU displayed strong synergistic effects on the in vitro induction of U87 glioma cell apoptosis as measured by an ELISA for DNA fragmentation. Therefore we assessed the effects of furegrelate alone and in combination with BCNU on the survival of human glioma bearing nude mice. While local delivery of furegrelate alone at 2 mg/kg/d for 28 days prolonged the survival only marginally, the combination with systemically administered BCNU (15 mg/kg/d) enhanced the survival more than the single compounds alone.

Conclusions

Our results indicate that targeting of the increased TXSA activity in human gliomas inhibits tumor growth in vivo by inducing pro-apoptotic, anti-proliferative and anti-angiogenic effects. Local treatment with a TXSA inhibitor has the potential to enhance conventional chemotherapeutic schemes for malignant gliomas. Future studies need to evaluate modern modulators of TXSA activity and address their effects in relationship to other metabolites of the arachidonic acid pathway.