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Riluzole: A Potent Anti-Brain Tumor Agent?

Nagendra Ningaraj, PhD, and Asha Das, MD

Many of the 35,000 Americans a year diagnosed with brain tumors, such as anaplastic astrocytoma and glioblastoma multiforme (GBM), face a bleak prognosis, despite treatment with maximal tumor resection, radiation and chemotherapy. A significant number of patients, after an initial surgical resection, end up with recurrent brain tumor. The one-year survival rate is less than 25% in patients with recurrent anaplastic astrocytoma and GBM. These tumors grow by infiltration or by expansion into adjacent normal cells. Malignant gliomas typically invade adjacent brain tissue, and 90% of recurrences occur within 2 cm of the original tumor site. A major setback to the treatment of a brain tumor is its aggressive proliferative behavior aided by several factors, including the release of excessive glutamate, which is highly toxic to normal cells surrounding the tumor.

Glutamate is a neurotoxin that is implicated in stroke, head trauma and several neurodegenerative diseases. In animal models, implanted glioma cells secrete glutamate, and glutamate levels are increased in and around these tumors. Several factors may contribute to the increased peritumoral glutamate levels, including increased secretion of glutamate into the extracellular space and decreased uptake by tumor cells from the extracellular space. In tumor cells, glutamate uptake is up to 100-fold lower than in normal astrocytes with reduced expression or mislocalization of glutamate transporters, including GLT-1 and GLAST (1,2). It is hypothesised that GBM's highly proliferative/aggressive behavior is due to excessive glutamate release and their ability to underexpress glutamate transporters so that they are not taken up by the glioma cells. Recently glutamate receptor antagonists were shown to slow glioma growth in an animal xenograft model. In particular, the NMDA receptor antagonist (MK801, memantine) was shown to block tumor growth in rats harboring RG2 glioma (1). The excessive release of glutamate by glioma results in destruction of neighboring healthy cells and is responsible for aggressive tumor growth. In animal models, when gliomas that actively released glutamate were compared with those that showed enhanced uptake of glutamate, tumors with high glutamate release were larger and associated with a shorter survival time than tumors with low glutamate release. There are several glutamate receptors, including N-methyl D-aspartate (NMDA), kainate, AMPA and metabotropic receptors. The NMDA receptor is a major subtype of glutamate receptor. It is possible that inhibiting glutamate secretion using NMDA receptor antagonists may prevent tumor expansion and tumor-associated necrosis. In fact, in mouse models treatment with a NMDA receptor antagonist slowed the growth of glutamate-secreting tumors in situ (3,4). Studies by others, however, have not demonstrated the role of glutamate release or glutamate transporters in GBM's highly proliferative behavior. Potential glioma treatment might be developed by:

• Activation of neuronal or astroglial glutamate transporters
• Inhibition of glutamate synthesis by disruption of precursor, glutamine supply via glutamine
• Inhibition of glutamine synthetase or phosphate-activated glutaminase transporters

Most notably, however, several 'on-the-shelf' glutamate receptor antagonists for potential glioma treatment could be developed fairly rapidly.

Glutamate plays an integral role in learning and memory. Excessive amounts of glutamate can damage cells by causing overstimulation. Presumably, the excitotoxicity produced by glutamate is responsible for the neuronal cell death. This excessive amount of glutamate may be responsible for the significant cognitive deficits that can be associated with brain tumors, even though the tumors may be small and without significant cerebral edema. In animal models, low-affinity, non-competitive NMDA receptor antagonists are thought to be neuroprotective against subchronic-glutamate toxicity and may result in symptomatic improvement of cognition in animal models (5). For this reason, in addition to the potential benefits to reduce or limit tumor growth, glutamate antagonists may potentially improve neurologic function in patients with brain tumors.

One such glutamate antagonist candidate for brain tumor treatment is Riluzole, which has been approved by the U.S. Food and Drug Administration for the treatment of amyotrophic lateral sclerosis (ALS), that acts by inhibiting voltage-activated sodium channel to block glutamate release. We are currently investigating whether Riluzole blocks glutamate release and enhances survival in GBM patients. Researchers at the Maxine Dunitz Neurosurgical Institute are performing preclinical studies on the effect of Riluzole in an animal xenograft GBM model. Preliminary results indicate that GBM cells isolated from GBM tissue dissected from patients show dramatic increase in glutamate release.

Figure I: Glutamate release immunostained with anti-glutamate antibody is shown in GBM primary cells. The glutamate released by GBM cells were stained with DAB-Ni stain using ABC staining method.

The MDNSI team is developing a clinical protocol to administer Riluzole to patients with recurrent GBM and anaplastic astrocytoma (AA) to determine its effects on tumor growth and survival among patients with AA or GBM. It is speculated that Riluzole will inhibit tumor progression and growth. If so, it holds great promise for treating brain tumors, especially the most aggressive forms, such as GBM and AA. 

References

1) Ye ZC, Sontheimer H. Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 1999;59:4383-4391. 

2) Behrens PF, Langemann H, Strohschein R, Draeger J, Hennig J. Extracellular glutamate and other metabolites in and around RG2 rate glioma: an intracerebral microdialysis study. J Neuroncol 2000;47:11-22. 

3) Takano T, Lin JH, Arcuino G, Gao Q, Yang J, Nedergaard M. Glutamate release promotes growth of malignant gliomas. Nat Med 2001;7(9):1010-5. 

4) Aronica E, Yankaya B, Jansen GH, Leenstra S, van Veelen CW, Gorter JA, Troost D. Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy. Neuropathol Appl Neurobiol 2001;27(3):223-37. 

5) Muller WE, Mutschler E, Riederer P. Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer's dementia. Pharmacopyschiatry 1995;28(4):113-24. 


Nagendra Ningaraj, PhD, is a research scientist, and Asha Das, MD, is a neuro-oncologist, both at the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center in Los Angeles. 
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