© 2005 by the Society forNeuro-Oncology
Pharmacological blockade of group II metabotropic glutamate receptorsreduces the growth of glioma cells in vivo
I.N.M. Neuromed, Località Camerelle, 86077Pozzilli (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 Physiologyand Pharmacology, University of Rome La Sapienza, Piazzale Aldo Moro 5, 00185Roma, Italy(ferdinandonicoletti{at}hotmail.com).
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Abstract |
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U87MG human glioma cells in cultures expressed metabotropic glutamate(mGlu) receptors mGlu2 and mGlu3. Addition of the mGlu2/3 receptor antagonistLY341495 to the cultures reduced cell growth, expression of cyclin D1/2, andactivation of the MAP kinase and phosphatidylinositol-3-kinase pathways. Thisis in line with the evidence that activation of mGlu2/3 receptors sustainsglioma cell proliferation. U87MG cells were either implanted under the skin (1x 106 cells/0.5 ml) or infused into the caudate nucleus (0.5x 106 cells/5 µl) of nude mice. Animals were treated for28 days with mGlu receptor antagonists by means of subcutaneous osmoticminipumps. Treatments with LY341495 or (2S)-
-ethylglutamate(both infused at a rate of 1 mg/kg per day) reduced the size of tumors growingunder the skin. Infusion of LY341495 (10 mg/kg per day) also reduced thegrowth of brain tumors, as assessed by magnetic resonance imaging analysiscarried out every seven days. The effect of drug treatment was particularlyevident during the exponential phase of tumor growth, that is, between thethird and the fourth week following cell implantation. Immunohistochemicalanalysis showed that U87MG cells retained the expression of mGlu2/3 receptorswhen implanted into the brain of nude mice. These data suggest that mGlu2/3receptor antagonists are of potential use in the experimental treatment ofmalignant gliomas.
Received October 25, 2004; Accepted February 22, 2005
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