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 g/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. Key words: selective MMP inhibitor; pancreatic cancer; antitumor effectPancreatic cancer is characterized by extensive local invasion of adjacent structures, perineural invasion, early metastasis to liver and lymph nodes and a poor prognosis. 1,2 The ability of tumor cells to degrade adjacent extracellular matrix is considered an essential step in the processes of invasion and metastasis. 3,4 Matrix metalloproteinases (MMPs) are a family of structurally related zymogens capable of degrading extracellular matrix, including basement membrane. They are secreted by cancer cells and adjacent stromal cells in latent form and then converted into their active form. MMPs are crucial for tumor cell migration through the basement membrane and extracellular matrix, and for tumor cell intravasation and extravasation. 3,5 MMP-2-degrading type IV collagen, which is a main component of basement membranes, is expressed in pancreatic cancer 6 and plays an important role in invasion and metastasis. 7,8 MMPs also appear to be involved in angiogenesis, by mediating tissue remodeling and penetration of the extracellular matrix by activated endothelial cells. 4 Angiogenesis, which is essential for tumor growth and metastasis, is one of the important steps in the transition of tumors from small, harmless clusters of mutated cells to large, malignant growths, capable of spreading to other organs throughout the body. 9 When angiogenesis is blocked, tumor growth is suppressed, and tumor cell proliferation is balanced by apoptosis. 10 MMP-2 plays an especially important role in angiogenesis and tumor progression in some cancers. 11 Hamster pancreatic cancer cell line PGHAM-1 was derived from BOP (N-nitrosobis(2-oxopropyl)amine)-induced hamster pancreatic cancer cells as a result of repeated passage by subcutaneous implantation. It is a ductal adenocarcinoma that closely resembles human pancreatic carcinoma, and it often gives rise to liver metastasis shortly after implantation into the pancreas. [12][13][14] The PGHAM-1 cell line is useful for studying pancreatic cancer and liver metastasis by pancreatic cancer.Many studies have been conducted on the inhibitory effect of MMP inhibitors on invasion and metastasis in var...

Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer

“…Some studies have reported that lymph node metastasis in lung cancer closely correlated with the activation of MMP-2 and MT1-MMP, which are specific activators of MMP-2 on the cell surface (5,6). We speculated that MMI-166 with the inhibitory potential of MMP-2 activity contributes to the suppression of mediastinal lymph node metastasis in lung cancer, whereas previous reports show that MMI-166 inhibits tumor angiogenesis (22,23). The mechanism inhibiting lymph node metastasis in this study may include both the suppression of extracellular matrix degradation and the inhibition of angiogenesis at metastatic sites.…”

“…There are several classes of agents which target the different steps involved in angiogenesis (21). These include (a) drugs inhibiting MMP, (b) drugs that block endothelial cell signaling by vascular endothelial growth factor and its receptor, (c) drugs that are similar to (22,23). This study also showed that the Ma44-3 lung cancer cell line moderately expressed both MMP-9 and MMP-2, and that 200 mg/kg body weight of MMI-166 significantly suppressed the Mediastinal metastatic lesions in the control group showed gelatinolytic activity on GN film, whereas mediastinal metastasis in the MMP-166 group showed no activity on GN film.…”

“…Matsuoka et al showed that a MMPI, R-94138, inhibited lymph node metastasis of gastric cancer in an orthotopically implanted model (13). MMI-166 has also been reported to inhibit the hematogenous metastasis of various cancers in animal models (12,22,27), there has been no report evaluating whether or not MMI-166 inhibits lymphogenous metastasis until now. This study showed that MMI-166 significantly inhibited mediastinal lymph node metastasis in an orthotopically implanted lung cancer model of the Ma44-3 cell line with MMP-2 and MMP-9 activities, and it strongly inhibited gelatinolytic activity localized in mediastinal metastatic lesions.…”

Adeno-Associated Viral Vector-Mediated Expression of Endostatin Inhibits Tumor Growth and Metastasis in an Orthotropic Pancreatic Cancer Model in Hamsters

“…The PGHAM-1 cell line (the hamster pancreatic cancer cell line) was derived from hamster pancreatic cancer cells induced with N-nitrosobis(2-oxopropyl)amine (12). Hamsters were anesthetized with Nembutal and then underwent laparotomy.…”

“…When PGHAM-1 derived from chemically induced hamster pancreatic cancer cells (11) is injected into the pancreas of hamsters, the cells develop ductal adenocarcinoma that closely resembles human pancreatic carcinoma and, like its human counterpart, frequently metastasizes to the liver. Thus, hamsters inoculated with PGHAM-1 cells represent an orthotopic pancreatic cancer model (12).…”