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. T his study investigates the impact of the MMP-inhibitor Batimastat and/or th e 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 activi ty of the tumor cells was determined buy caseinolytic and collagenolytic in vitro assays and tumor cel invasion by intraperitoneal inoculation of the tumor cells into nude mice. In vitro, Aprotinin, tested alone or in combina tion with Batimastat, efficiently inhibited degradation of collagen IV and casein by the tumor cells. Batimastat alone had no effect on caseinolytic a ctivities and only partially blocked collagen-type-IV-degradation by the tu mor cells. In vivo, Aprotinin tested alone or in combination with Batimasta t die not prevent tumor cel invasion. Treatment of tumor bearing mice with Batimastat significantly inhibited tumor growth but promoted tumor cell inv asion 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.