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Eur J Cancer. 2013 Jun;49(9):2243-52. doi: 10.1016/j.ejca.2013.02.019. Epub 2013 Mar 14.

Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas.

Author information

  • 1Department of Neurosurgery, Universitätsmedizin Charité, Berlin, Germany.
  • 2Institut National de la Santé et de la Recherche Médicale, Talence, France; Université de Bordeaux, Talence, France.
  • 3Center for Stroke Research, Universitätsmedizin Charité, Berlin, Germany.
  • 4Department of Neurology, Universitätsmedizin Charité, Berlin, Germany.
  • 5Department of Neuropathology, Universitätsmedizin Charité, Berlin, Germany.
  • 6Department of Neurosurgery, Universitätsmedizin Charité, Berlin, Germany. Electronic address: peter.vajkoczy@charite.de.

Abstract

INTRODUCTION:

Combined antiangiogenic and cytotoxic treatment represents an appealing treatment approach for malignant glioma. In this study we characterised the antitumoural and microvascular consequences of sunitinib (Su) and temozolomide (TMZ) therapy and verified the ideal treatment protocol, with special focus on a potential therapeutic window for combined scheduling.

MATERIALS AND METHODS:

O(6)-Methylguanine methyltransferase (MGMT) status was analysed by pyrosequencing. Tumour growth of subcutaneous xenografts was assessed under different treatment protocols (TMZ, SU, SU followed by TMZ, TMZ followed by SU, combined TMZ/SU). Intravital microscopy (dorsal skinfold chamber model) assessed microvascular consequences. Immunohistochemistry included tumour and endothelial cell proliferation, apoptosis and vascular pericyte coverage. Real-time polymerase chain reaction (RT-PCR) analysed the expression of angiogenesis-related pathways in response to therapy.

RESULTS:

Combined TMZ/SU resulted in significantly reduced tumour growth compared to either monotreatment (TMZ: 106 ± 13 mm(3); SU: 114 ± 53 mm(3); TMZ/SU: 34 ± 7 mm(3)) by additional antiangiogenic effects and synergistic induction of apoptosis versus TMZ monotreatment. Sequential treatment protocols did not show additive antitumour responses. TMZ/SU aggravated vascular resistance mechanisms characterised by significantly higher blood flow rate (TMZ: 74 ± 34 μl/s; SU: 164 ± 36 μl/s; TMZ/SU: 254 ± 95 μl/s), reduced permeability (TMZ: 1.05 ± 0.02; SU: 0.99 ± 0.07; TMZ/SU: 0.89 ± 0.05) and recovery of pericyte-endothelial interactions (TMZ: 89 ± 7%; SU: 67 ± 9%, TMZ/SU:80 ± 10%) versus either monotreatment. Vascular resistance was paralleled by an increase in Ang-1 and Tie-2 and by the downregulation of Dll4.

CONCLUSION:

Sequential application of TMZ and SU in the angiogenic window does not add antitumour efficacy to monotherapy. Simultaneous application yields beneficial tumour control due to additive antiangiogenic and proapoptotic effects. Combined treatment may aggravate pericyte-mediated vascular resistance mechanisms by altering Ang-1-Tie-2 and Dll4/Notch pathways.

Copyright © 2013 Elsevier Ltd. All rights reserved.

PMID:
23499430
[PubMed - indexed for MEDLINE]
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