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. Summary Background Data Inhibitors of MMPs, enzymes that degrade extracellular matrix, have been te sted as single chemotherapeutic agents for pancreatic cancer. Methods 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). Results 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. Conclusions 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.