SI-27, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity: detection with a variable-pressure scanning electron microscope.
OBJECTIVE
Degradation of basement membrane is one the of crucial steps in tumor angiogenesis and is performed by matrix metalloproteinases (MMPs). This study was designed to investigate the suppression of tumor angiogenesis by SI-27, an MMP inhibitor.


METHODS
SI-27 was applied at noncytotoxic concentrations (1-100 micromol/L), and its effect on nonmitogenic vascular endothelial growth factor (VEGF)-enhanced cell motility and in vitro angiogenesis by human umbilical vein endothelial cells was determined. The activity of MMP-1, MMP-2, and tissue inhibitor of metalloproteinase 1 was determined by enzyme-linked immunosorbent assay. The effect of SI-27 on in vitro angiogenesis stimulated by supernatants of human glioma cell lines (U87MG, U251MG, and U373MG) also was examined. Angiogenesis was detected with variable vacuum scanning electron microscopy.


RESULTS
Cell motility and in vitro angiogenesis by human umbilical vein endothelial cells were significantly increased by VEGF. The maximal effect on cell motility by VEGF was noted at 5 ng/ml (P < 0.001), and the maximal effect on the capillary network was observed at 10 ng/ml (P < 0.001), along with elevated MMP-1 and MMP-2 activity. Whereas SI-27 significantly suppressed VEGF-mediated in vitro angiogenesis (50 micromol/L; P < 0.001) and inactivated both MMP-1 and MMP-2, the expression of tissue inhibitor of metalloproteinase 1 and VEGF-mediated cell motility were not affected by SI-27. The angiogenesis promoted by glioma supernatants showed a significant reduction in the presence of SI-27 (10 micromol/L; U87MG, P < 0.01; U251MG, P < 0.01; U373MG, P < 0.01).


CONCLUSIONS
SI-27 inhibited in vitro tumor angiogenesis by suppression of MMP. This agent may be anticipated to prevent tumor growth through an angiosuppressive effect.
Yoshida
Daizo
D
Department of Neurosurgery, Nippon Medical School, Tokyo, Japan. dyoshida@nms.ac.jp
Noha
Masahiro
M
Watanabe
Kunihiro
K
Sugisaki
Yuichi
Y
Teramoto
Akira
A
D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005910:Glioma / Q000098:blood supply / Q000648:ultrastructure; D006801:Humans; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D011480:Protease Inhibitors; C421267:SI 27; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020782:Matrix Metalloproteinases