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Inhibition of Glioma Angiogenesis and Invasion by SI-27, an Anti-matrix Metalloproteinase Agent in a Rat Brain Tumor Model.


Posted on: 05/05/2004

Inhibition of Glioma Angiogenesis and Invasion by SI-27, an Anti-matrix Metalloproteinase Agent in a Rat Brain Tumor Model.

Neurosurgery. 2004 May;54(5):1213-22.

Yoshida D, Takahashi H, Teramoto A.
Department of Neurosurgery, Nippon Medical School, Tokyo, Japan.

OBJECTIVE: The matrix metalloproteinase (MMP) inhibitor SI-27 has undergone extensive development because of its effectiveness against glioma invasion and angiogenesis. However, previous studies have been performed in vitro. The present work investigates the potential of SI-27 to inhibit tumor invasion, slow angiogenesis, and prolong survival in rodent brain tumor models.

METHODS: Stable enhanced green fluorescent protein-expressing clones of a human malignant glioma cell line, U251MG, were stereotactically xenografted into the periphery of the anterior striatum and corpus callosum of Fischer 944 rats after immunosuppression with cyclosporin A. SI-27 (1 or 10 mg/kg) or carrier solution was administered on three successive days by intraperitoneal injection, and tumor invasion and angiogenesis were assessed 3 weeks later by quantitative image analysis. This was performed on whole brain sections analyzed either by direct observation of enhanced green fluorescent protein-expressing glioma cells or by additional immunohistochemistry to detect the endothelial cells with anti-factor VIII monoclonal antibody. In situ zymography on frozen sections was used to detect MMP activity.

RESULTS: The group receiving a total of 30 mg/kg showed a statistically significant (P < 0.001) increase in survival time compared with the controls receiving carrier (median survival, 47.3 versus 32.6 d). There was also a decrease in MMP activity, tumor cell invasion, and neovascularization. In contrast, animals given 3 mg/kg did not show these differences. CONCLUSION: Systemic administration of the anti-MMP agent SI-27 is effective in the treatment of glioma in an animal model.

PMID: 15113477 [PubMed]

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