Inhibition of glioma angiogenesis and invasion by SI-27, an anti-matrix metalloproteinase agent in a rat brain tumor model.
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.


CONCLUSIONS
Systemic administration of the anti-MMP agent SI-27 is effective in the treatment of glioma in an animal model.
Yoshida
Daizo
D
Department of Neurosurgery, Nippon Medical School, Tokyo, Japan. dyoshida@nms.ac.jp
Takahashi
Hiroshi
H
Teramoto
Akira
A
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005169:Factor VIII / Q000378:metabolism; D005910:Glioma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009842:Oligopeptides / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection
D008164:Luminescent Proteins; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; C421267:SI 27; D049452:Green Fluorescent Proteins; D005169:Factor VIII; D020782:Matrix Metalloproteinases