Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model.
OBJECTIVE
The aims of the present work were to investigate the in vitro and in vivo antiangiogenic effects of chronic temozolomide treatment on various glioma models and to demonstrate whether bevacizumab (Avastin) increased the therapeutic benefits contributed by temozolomide in glioma.


METHODS
The expression levels of various antiangiogenic factors in four glioma cell lines were evaluated after chronic in vitro treatment with temozolomide by Western blot. Proliferation and migration assays were performed on human endothelial cells incubated with supernatants of glioma cells treated with and without temozolomide. Orthotopic glioma models were used to evaluate the antiangiogenic effects of temozolomide in vivo and the therapeutic benefits of different temozolomide treatment schedules used alone or in combination with bevacizumab.


RESULTS
Temozolomide, a proautophagic and proapoptotic drug, decreased the expression levels of HIF-1alpha, ID-1, ID-2, and cMyc in the glioma models investigated, all of which playing major roles in angiogenesis and the switch to hypoxic metabolism. These changes could be, at least partly, responsible for the impairment of angiogenesis observed in vitro and in vivo. Moreover, combining bevacizumab with temozolomide increased the survival of glioma-bearing mice in comparison to each compound administered alone.


CONCLUSIONS
In addition to the numerous mechanisms of action already identified for temozolomide, we report here that it also exerts antitumor effects by impairing angiogenic processes. We further emphasize that bevacizumab, which is an antiangiogenic drug with a different mechanism of action, could be useful in combination with temozolomide to increase the latter's therapeutic benefit in glioma patients.
Mathieu
Véronique
V
Laborarory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium.
De Nève
Nancy
N
Le Mercier
Marie
M
Dewelle
Janique
J
Gaussin
Jean-François
JF
Dehoux
Mischael
M
Kiss
Robert
R
Lefranc
Florence
F
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D000077204:Temozolomide
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003606:Dacarbazine; D000077204:Temozolomide