title: 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.affiliation: Department of Surgery, University of South Florida, and James A. Haley Veteran's Administration Medical Center, Tampa, Florida, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Zervos
authors.forename: A E
authors.initials: AE
authors.lastname: Shafii
authors.forename: A S
authors.initials: AS
authors.lastname: Rosemurgy
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D017364:Collagenases / Q000378:metabolism*; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9