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

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-I, In vitro, MMI-166 inhibited the gelat inase activity of MMP-2 and -9 derived from PGHAM-I cells, and dose-depende ntly inhibited invasion of PGHAM-I through a basement membrane-like barrier . MMI-166 showed no apparent cytotoxicity to PGHAM-I cells in culture at 10 0 mug/ml. MMI-166 (200 mg/kg) or vehicle were administered orally, once dai ly, from day I until day 21 after implantation in the orthotopic implantati on model of PGHAM-I. MMI-166 significantly reduced the incidence of liver s urface metastasis from 66.7% to 20.0%, and it reduced the number of liver s urface 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 densi ty from 37.90 +/- 10.18/mm(2) to 16.16 +/- 3.15/mm(2) and a significant inc rease in apoptotic index from 1.75 +/- 0.41% to 3.96 +/- 0.38%, but there w as no significant difference between tumor cell proliferation in the MMI-16 6-group and the control group. These results showed that selective MMP inhi bition 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 inv asion and angiogenesis, (C) 2001 Wiley-Liss. Inc.