Anti-invasive and antiangiogenic effects of MMI-166 on malignant glioma cells.
BACKGROUND
The constitutive overexpression of matrix metalloproteinases (MMPs) is frequently observed in malignant tumours. In particular, MMP-2 and MMP-9 have been reported to be closely associated with invasion and angiogenesis in malignant gliomas. Our study aimed to evaluate the antitumour effects of MMI-166 (Nalpha-[4-(2-Phenyl-2H- tetrazole-5-yl) phenyl sulfonyl]-D-tryptophan), a third generation MMP inhibitor, on three human glioma cell lines (T98G, U87MG, and ONS12) in vitro and in vivo.


METHODS
The effects of MMI-166 on the gelatinolytic activity was analysed by gelatine zymography. The anti-invasive effect of MMI-166 was analysed by an in vitro invasion assay. An in vitro angiogenesis assay was also performed. In vitro growth inhibition of glioma cells by MMI-166 was determined by the MTT assay. The effect of MMI-166 on an orthotropic implantation model using athymic mice was also evaluated.


RESULTS
Gelatine zymography revealed that MMP-2 and MMP-9 activities were suppressed by MMI-166. The invasion of glioma cells was suppressed by MMI-166. The angiogenesis assay showed that MMI-166 had a suppressive effect on glioma cell-induced angiogenesis. However, MMI-166 did not suppress glioma cell proliferation in the MTT assay. In vivo, MMI-166 suppressed tumour growth in athymic mice implanted orthotropically with T98G cells and showed an inhibitory effect on tumour-induced angiogenesis and tumour growth. This is the first report of the effect of a third generation MMP inhibitor on malignant glioma cells.


CONCLUSIONS
These results suggest that MMI-166 may have potentially suppressive effects on the invasion and angiogenesis of malignant gliomas.
Nakabayashi
Hiromichi
H
Department of Neurosurgery, Kochi Medical School Kochi University, Nankoku, Japan. blue_flare17@yahoo.co.jp
Yawata
Toshio
T
Shimizu
Keiji
K
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005910:Glioma / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D013449:Sulfonamides / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C419963:N-alpha-(4-(2-phenyl-2H- tetrazole-5-yl) phenyl sulfonyl)-D-tryptophan; D013449:Sulfonamides