Antitumor effect of a new selective matrix metalloproteinase inhibitor, MMI-166, on experimental pancreatic cancer.

Abstract

The antitumor effect of a new matrix metalloproteinase inhibitor, MMI-166, which is a selective inhibitor of MMP-2 and -9, was examined in the hamster pancreatic cancer cell line PGHAM-1. In vitro, MMI-166 inhibited the gelatinase activity of MMP-2 and -9 derived from PGHAM-1 cells, and dose-dependently inhibited invasion of PGHAM-1 through a basement membrane-like barrier. MMI-166 showed no apparent cytotoxicity to PGHAM-1 cells in culture at 100 microgram/ml. MMI-166 (200 mg/kg) or vehicle were administered orally, once daily, from day 1 until day 21 after implantation in the orthotopic implantation model of PGHAM-1. MMI-166 significantly reduced the incidence of liver surface metastasis from 66.7% to 20.0%, and it reduced the number of liver surface metastases per animal from 6.17 to 2.00, but this reduction was not significant. MMI-166 significantly reduced the volume of pancreatic tumors from 718.3 +/- 220.0 mm(3) to 222.8 +/- 85.4 mm(3). Treatment of pancreatic tumors with MMI-166 caused a significant reduction in the microvessel density from 37.90 +/- 10.18/mm(2) to 16.16 +/- 3.15/mm(2) and a significant increase in apoptotic index from 1.75 +/- 0.41% to 3.96 +/- 0.38%, but there was no significant difference between tumor cell proliferation in the MMI-166-group and the control group. These results showed that selective MMP inhibition could limit both cancer spread and angiogenesis in pancreatic cancer. The selective MMP-2 and -9 inhibitor MMI-166 may be of therapeutic use in the treatment of pancreatic cancer because of its inhibitory effect on invasion and angiogenesis.

• Authors: A Matsushita, M Onda, E Uchida, R Maekawa, T Yoshioka
• Journal: International journal of cancer (Int J Cancer) Vol. 92 Issue 3 Pg. 434-40 (May 01 2001) ISSN: 0020-7136 [Print] United States
• PMID: 11291083 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2001 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Matrix Metalloproteinase Inhibitors
• N-alpha-(4-(2-phenyl-2H- tetrazole-5-yl) phenyl sulfonyl)-D-tryptophan
• Sulfonamides

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis
• Cell Division (drug effects)
• Cricetinae
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Female
• Immunohistochemistry
• Matrix Metalloproteinase Inhibitors
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Pancreatic Neoplasms (drug therapy, pathology)
• Silver Staining
• Sulfonamides (therapeutic use)
• Tumor Cells, Cultured