A Potent Anti-Brain Tumor Agent?
Ningaraj, PhD, and Asha Das, MD
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
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:
of neuronal or astroglial glutamate transporters
of glutamate synthesis by disruption of precursor, glutamine supply via
of glutamine synthetase or phosphate-activated glutaminase transporters
notably, however, several 'on-the-shelf' glutamate receptor antagonists for
potential glioma treatment could be developed fairly rapidly.
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.
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.
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.
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.
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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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