Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models.
OBJECTIVE
The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models.


METHODS
In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT).


RESULTS
In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival.


CONCLUSIONS
Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone.
Department of Pediatrics, Weill Cornell Medical College;
Kaleb
K
Yohay
Betty
B
Tyler
Kyle D
KD
Weaver
Andrea C
AC
Pardo
Dan
D
Gincel
Jaishri
J
Blakeley
Henry
H
Brem
Jeffrey D
JD
Rothstein
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy*; D008559:Memantine / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D011108:Polymers / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D019782:Riluzole / Q000008:administration & dosage / Q000627:therapeutic use*
D018691:Excitatory Amino Acid Antagonists; D011108:Polymers; D019782:Riluzole; D008559:Memantine