Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: an additive strategy for cancer control.
OBJECTIVE
To investigate the effect of a matrix metalloproteinase (MMP) inhibitor, BB-94, on the viability, invasion, and metastases of pancreatic cancer.


BACKGROUND
Inhibitors of MMPs, enzymes that degrade extracellular matrix, have been tested as single chemotherapeutic agents for pancreatic cancer.


METHODS
Capan1 and AsPC1 cell lines were studied. BB-94 cytotoxicity was evaluated by cell proliferation assays. Production of MMP2 and MMP9 in conditioned media was demonstrated by gelatin zymography. The in vitro effect of BB-94 on cell invasion was assayed using invasion chambers. Hepatic metastases from pancreatic cancer were induced by intrasplenic injections of Capan1 or AsPC1 cells in nude mice. The in vivo effect of BB-94 on liver metastases was evaluated by comparing animals receiving BB-94 treatment with controls receiving vehicle alone. Variables measured included death rate and tumor burden (liver-to-body weight ratio).


RESULTS
BB-94 was not cytotoxic between 3 and 3,000 ng/mL. Zymography demonstrated production of MMP2 and MMP9 by both cell lines, with complete inhibition of these enzymes by BB-94 at 48 ng/mL. Invasion chamber assays showed that BB-94 (48-400 ng/mL) impeded cell invasion in vitro compared with untreated controls. In vivo, BB-94 prevented death or reduced the death rate from hepatic metastases in animals injected with Capan1 or AsPC1 cells. BB-94 treatment resulted in significant reductions in hepatic tumor burden compared with untreated controls.


CONCLUSIONS
Inhibition of MMP reduces both growth of pancreatic cancer metastases and the death rate. These actions do not reflect cytotoxicity but rather result from impaired cancer cell attachment, migration, and organ invasion. MMP inhibitors may provide an additive effect to cytotoxic agents in multidimensional treatment regimens for pancreatic cancer.
Jimenez
R E
RE
Departments of Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Hartwig
W
W
Antoniu
B A
BA
Compton
C C
CC
Warshaw
A L
AL
Fernández-Del Castillo
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000556:secondary*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D008666:Metalloendopeptidases