To investigate the effect of a matrix metalloproteinase (MMP) inhibitor, BB
-94, on the viability, invasion, and metastases of pancreatic cancer.
Summary Background Data
Inhibitors of MMPs, enzymes that degrade extracellular matrix, have been te
sted as single chemotherapeutic agents for pancreatic cancer.
Capan1 and AsPC1 cell lines were studied, BE-94 cytotoxicity was evaluated
by cell proliferation assays. Production of MMP2 and MMP9 in conditioned me
dia was demonstrated by gelatin zymography. The in vitro effect of BE-94 on
cell invasion was assayed using invasion chambers. Hepatic metastases from
pancreatic cancer were induced by intrasplenic injections of Capan1 or AsP
C1 cells in nude mice. The in vivo effect of BE-94 on liver metastases was
evaluated by comparing animals receiving BE-94 treatment with controls rece
iving vehicle alone. Variables measured included death rate and tumor burde
n (liver-to-body weight ratio).
BE-94 was not cytotoxic between 3 and 3,000 ng/ml, Zymography demonstrated
production of MMP2 and MMPS by both cell lines, with complete inhibition of
these enzymes by 88-94 at 48 ng/ml. Invasion chamber assays showed that 88
-94 (48-400 ng/mi) impeded cell invasion in vitro compared with untreated c
ontrols. In vivo, BE-94 prevented death or reduced the death rate from hepa
tic metastases in animals injected with Capan1 or AsPC1 cells, BE-94 treatm
ent resulted in significant reductions in hepatic tumor burden com pared wi
th untreated controls.
Inhibition of MMP reduces both growth of pancreatic cancer metastases and t
he death rate. These actions do not reflect cytotoxicity but rather result
from impaired cancer cell attachment, migration, and organ invasion. MMP in
hibitors may provide an additive effect to cytotoxic agents in multidimensi
onal treatment regimens for pancreatic cancer.