Matrix metalloproteinase inhibition attenuates human pancreatic cancer growth in vitro and decreases mortality and tumorigenesis in vivo.
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.
Zervos
E E
EE
Department of Surgery, University of South Florida, Tampa 33601, USA.
Norman
J G
JG
Gower
W R
WR
Franz
M G
MG
Rosemurgy
A S
AS
D000818:Animals; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D009362:Neoplasm Metastasis; 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
D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D008666:Metalloendopeptidases