Combined treatment with serine protease inhibitor aprotinin and matrix metalloproteinase inhibitor Batimastat (BB-94) does not prevent invasion of human esophageal and ovarian carcinoma cells in vivo.
Many studies have highlighted the role played by matrix metalloproteinases MMP-2 and -9, by serine proteases uPA and plasmin in tumor cell invasion. This study investigates the impact of the MMP-inhibitor Batimastat and/or the serine protease inhibitor Aprotinin on the in vitro proteolytic activity and in vivo invasive behavior the of esophageal (OC1) and ovarian (OVCAR-3) carcinoma cells. In presence and absence of inhibitors, proteolytic activity of the tumor cells was determined by caseinolytic and collagenolytic in vitro assays and tumor cell invasion by intraperitoneal inoculation of the tumor cells into nude mice. In vitro, Aprotinin, tested alone or in combination with Batimastat, efficiently inhibited degradation of collagen IV and casein by the tumor cells. Batimastat alone had no effect on caseinolytic activities and only partially blocked collagen-type-IV-degradation by the tumor cells. In vivo, Aprotinin tested alone or in combination with Batimastat did not prevent tumor cell invasion. Treatment of tumor bearing mice with Batimastat significantly inhibited tumor growth but promoted tumor cell invasion into the liver. Our findings demonstrate that the inhibition pattern of cellular proteolytic activity achieved in vitro by a serine protease and an MMP inhibitor may lead to predictions that are not necessarily verified in vivo and may even have adverse effects.
Della Porta
P
P
Klinische Forschergruppe, Technischen Universität München, Germany.
Soeltl
R
R
Krell
H W
HW
Collins
K
K
O'Donoghue
M
M
Schmitt
M
M
Krüger
A
A
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010958:Plasminogen / Q000494:pharmacology; D010960:Plasminogen Activators / Q000096:biosynthesis; D011480:Protease Inhibitors / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; D010958:Plasminogen; D003094:Collagen; D007611:Aprotinin; C080985:batimastat; D010960:Plasminogen Activators; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9