Matrix metalloproteinase (MMP) inhibition selectively decreases type II MMP activity in a murine model of pancreatic cancer.

Abstract

BACKGROUND:

Basement membrane degradation is a critical component of tumor invasion and metastasis that is facilitated by the family of enzymes known as matrix metalloproteinases (MMPs). MMP-2 and MMP-9 are two subtypes that have specifically been identified in tumors of gastrointestinal origin. We have previously shown that broad inhibition of these enzymes with the MMP inhibitor BB-94 improves survival in a murine model of pancreatic cancer. The purpose of this study was to determine MMP-2 and MMP-9 activity in orthotopic tumors from mice treated with and without BB-94.

METHODS:

Ten million cells of a moderately differentiated pancreatic cancer cell line (HPAC) were implanted orthotopically into Balb/c nu/nu mice. The mice were treated with BB-94 or vehicle control for 70 days or until death. At necropsy, tumors were harvested, total protein was extracted, and MMPs were purified from 400 microgram of crude protein extract by gelatin-Sepharose affinity chromatography. Relative enzyme levels and activity of MMP-2 and MMP-9 were determined by Western blot and gelatin zymography.

RESULTS:

Tumors from treated animals were significantly smaller than those from nontreated animals. MMP-2 was present in greater amounts in both treated and nontreated animals than MMP-9. Active MMP-2 was present in both groups but significantly decreased in animals treated with BB-94. Active MMP-9 was absent in both groups, whereas levels of latent MMP-9 appeared lower than those of MMP-2 in all samples.

CONCLUSIONS:

Activated MMP-2 and not MMP-9 in HPAC cells grown in nude mice suggests that this MMP subtype is more critical in the phenotypic behavior of such tumors. Furthermore, attenuated levels of active MMP-2 in animals treated with the enzyme inhibitor BB-94 suggest that previously observed improvements in survival correlate with the level of MMP-2 activity.

• Authors: E E Zervos, A E Shafii, A S Rosemurgy
• Journal: The Journal of surgical research (J Surg Res) Vol. 81 Issue 1 Pg. 65-8 (Jan 1999) ISSN: 0022-4804 [Print] United States
• PMID: 9889060 (Publication Type: Journal Article)
• Copyright: Copyright 1999 Academic Press.

Chemical References

• Matrix Metalloproteinase Inhibitors
• Protease Inhibitors
• Thiophenes
• Phenylalanine
• batimastat
• Collagenases
• Gelatinases
• Metalloendopeptidases
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Adenocarcinoma (enzymology, pathology)
• Animals
• Blotting, Western
• Collagenases (metabolism)
• Gelatinases (antagonists & inhibitors, metabolism)
• Humans
• Male
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• Matrix Metalloproteinase Inhibitors
• Metalloendopeptidases (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Pancreatic Neoplasms (enzymology, pathology)
• Phenylalanine (analogs & derivatives, pharmacology)
• Protease Inhibitors (pharmacology)
• Thiophenes (pharmacology)
• Tumor Cells, Cultured