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-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.
Matsushita
A
A
Department of Surgery I, Nippon Medical School, Tokyo, Japan. matsushita_akira/surg1@nms.ac.jp
Onda
M
M
Uchida
E
E
Maekawa
R
R
Yoshioka
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D007150:Immunohistochemistry; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016622:Silver Staining; D013449:Sulfonamides / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C419963:N-alpha-(4-(2-phenyl-2H- tetrazole-5-yl) phenyl sulfonyl)-D-tryptophan; D013449:Sulfonamides