MATRIX METALLOPROTEINASE INHIBITION ATTENUATES HUMAN PANCREATIC-CANCER GROWTH IN-VITRO AND DECREASES MORTALITY AND TUMORIGENESIS IN-VIVO

Matrix metalloproteinases (MMP) are enzymes responsible for extracellu lar matrix degradation, a critical component influencing the growth an d metastatic potential of cancer, The purpose of this study was to det ermine the in vitro effects of MMP inhibition on human pancreatic canc er cells and to document its effect on cancer growth in vivo. The effe ct of MMP inhibition was determined using the MMP inhibitor BB-94 and a moderately differentiated pancreatic cancer cell line (HPAC). In vit ro, a dose response curve was generated over 5 days utilizing the,MTT (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. In vivo using an established orthotopic model for pancreatic cancer (LD10 0 = 80 days), 22 nude mice with orthotopic tumors (30 were implanted) received either BB-94 or vehicle beginning 4 days prior to implantatio n and continuing to death or sacrifice on Day 70. Mice were weighed we ekly, At death/sacrifice, tumors were weighed, volume determined, and metastases/distant spread documented, In vitro, BB-94 had little effec t on HPAC proliferation at 40 ng/ml but achieved progressively greater to near complete inhibition at doses up to 4000 ng/ml while maintaini ng cell viability. In vivo BB-94 significantly increased length of sur vival (69 +/- 0.1 days vs, 56 +/- 3.1 days) and necropsy weight (25.7 +/- 1.67 g vs. 19.8 +/- 1.14 g) while decreasing metastatic rate (I vs , 20) and tumor size (0.14 +/- 0.02 g vs. 0.65 +/- 0.1 g). MMP inhibit ion limits HPAC proliferation in a dose-dependent fashion without dire ct cytotoxic effects in vitro. Mice harboring orthotopic tumors treate d with BB-94 demonstrated significant reductions in tumor weight, volu me, and metastases which corresponded to increased animal weight and p rolonged survival. (C) 1997 Academic Press.