Matrix metalloproteinases (
MMP) are
enzymes responsible for extracellular matrix degradation, a critical component influencing the growth and metastatic potential of
cancer. The purpose of this study was to determine the in vitro effects of
MMP inhibition on human
pancreatic cancer cells and to document its effect on
cancer growth in vivo. The effect of
MMP inhibition was determined using the
MMP inhibitor BB-94 and a moderately differentiated
pancreatic cancer cell line (HPAC). In vitro, a dose response curve was generated over 5 days utilizing the MTT [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide] assay. In vivo, using an established orthotopic model for
pancreatic cancer (LD100 = 80 days), 22 nude mice with orthotopic
tumors (30 were implanted) received either
BB-94 or vehicle beginning 4 days prior to implantation and continuing to death or sacrifice on Day 70. Mice were weighted weekly. At death/sacrifice,
tumors were weighted, volume determined, and
metastases/ distant spread documented. In vitro,
BB-94 had little effect on HPAC proliferation at 40 ng/ml but achieved progressively greater to near complete inhibition at doses up to 4000 ng/ml while maintaining cell viability. In vivo,
BB-94 significantly increased length of survival (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 (1 vs. 20) and
tumor size (0.14 +/- 0.02 g vs. 0.65 +/- 0.1 g).
MMP inhibition limits HPAC proliferation in a dose-dependent fashion without direct cytotoxic effects in vitro. Mice harboring orthotopic
tumors treated with
BB-94 demonstrated significant reductions in
tumor weight, volume, and
metastases which corresponded to increased animal weight and prolonged survival.