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Medical Neuro-Oncology |
I.N.M. Neuromed, Località Camerelle, 86077 Pozzilli (A.A., G.B., M.D., R.T.N., V.B., F.G., F.N.); Department of Cellular Biology and Neuroscience (G.C., F.S.), Istituto Superiore di Sanità, 00161 Rome; Departments of Human Physiology and Pharmacology (V.B., P.C., F.N.) and Experimental Medicine and Pathology (F.G.), University of Rome La Sapienza, 00185 Rome; Italy
4 Address correspondence to Ferdinando Nicoletti, Department of Human Physiology and Pharmacology, University of Rome La Sapienza, Piazzale Aldo Moro 5, 00185 Roma, Italy (ferdinandonicoletti{at}hotmail.com).
Abstract
U87MG human glioma cells in cultures expressed metabotropic glutamate
(mGlu) receptors mGlu2 and mGlu3. Addition of the mGlu2/3 receptor antagonist
LY341495 to the cultures reduced cell growth, expression of cyclin D1/2, and
activation of the MAP kinase and phosphatidylinositol-3-kinase pathways. This
is in line with the evidence that activation of mGlu2/3 receptors sustains
glioma cell proliferation. U87MG cells were either implanted under the skin (1
x 106 cells/0.5 ml) or infused into the caudate nucleus (0.5
x 106 cells/5 µl) of nude mice. Animals were treated for
28 days with mGlu receptor antagonists by means of subcutaneous osmotic
minipumps. Treatments with LY341495 or (2S)-
-ethylglutamate
(both infused at a rate of 1 mg/kg per day) reduced the size of tumors growing
under the skin. Infusion of LY341495 (10 mg/kg per day) also reduced the
growth of brain tumors, as assessed by magnetic resonance imaging analysis
carried out every seven days. The effect of drug treatment was particularly
evident during the exponential phase of tumor growth, that is, between the
third and the fourth week following cell implantation. Immunohistochemical
analysis showed that U87MG cells retained the expression of mGlu2/3 receptors
when implanted into the brain of nude mice. These data suggest that mGlu2/3
receptor antagonists are of potential use in the experimental treatment of
malignant gliomas.
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