The farnesyltransferase inhibitor R115777 reduces hypoxia and matrix metalloproteinase 2 expression in human glioma xenograft.
OBJECTIVE
The high-grade primary brain tumors, glioblastoma, of extremely bad prognosis contain large regions of hypoxia known to be involved in the chemo- and radioresistance. We demonstrated previously that radioresistant human wild-type Ras U87 glioblastoma can be radiosensitized in vitro by the specific farnesyltransferase inhibitor R115777. The aim of this study was to analyze the effect of this compound on the hypoxic status and the vascularization of this tumor.


METHODS
U87 xenografts bearing mice were treated with 100 mg/kg of R115777 b.i.d. during 4 days. Hypoxia was assessed by measuring the binding of hypoxic cell marker pentafluorinated 2-nitroimidazole. Immunohistochemistry was performed to analyze angiogenesis and metalloproteinase-2 expression.


RESULTS
We demonstrated here that R115777 treatment induced a significant oxygenation of U87 xenografts (P<0.001) associated with a decrease of hypoxia-inducible factor 1alpha expression. This reduction of hypoxia was not due to a decrease of tumor size after R115777 treatment. This oxygenation was associated with a change in vessel morphology and with a significant decrease of the vessel density. Moreover, R115777 treatment reduced matrix metalloproteinase 2 expression in xenografts and inhibited matrix metalloproteinase 2 activity in vitro. These data strongly suggest that R115777 could increase this tumor oxygenation at least by interacting with angiogenesis.


CONCLUSIONS
Our results demonstrate that R115777 treatment inhibits different pathways leading to the radioresistance of wild-type Ras expressing glioblastoma, including intrinsic radioresistance, hypoxia, and angiogenesis. These combined effects on glioblastoma underline the interest of associating R115777 with radiotherapy as a new treatment of these tumors of catastrophic prognosis.
Delmas
Caroline
C
Laboratoire d'Oncologie Cellulaire et Moléculaire Institut National de la Santé et de la Recherche Médicale U593, Institut Claudius Regaud, Toulouse Cedex, France.
End
Dave
D
Rochaix
Philippe
P
Favre
Gilles
G
Toulas
Christine
C
Cohen-Jonathan
Elizabeth
E
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D007124:Immunoenzyme Techniques; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D020778:Matrix Metalloproteinase 2; C402769:tipifarnib; D010100:Oxygen