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Antitumor effect of a new selective matrix metalloproteinase inhibitor, MMI‐166, on experimental pancreatic cancer
Author(s) -
Matsushita A.,
Onda M.,
Uchida E.,
Maekawa R.,
Yoshioka T.
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1199
Subject(s) - pancreatic cancer , metastasis , matrix metalloproteinase inhibitor , matrix metalloproteinase , angiogenesis , gelatinase a , medicine , basement membrane , pathology , pancreatic disease , tissue inhibitor of metalloproteinase , apoptosis , cancer research , hamster , cancer , chemistry , pancreas , biochemistry
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 μg/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. © 2001 Wiley‐Liss, Inc.