Addition of matrix metalloproteinase inhibition to conventional cytotoxic therapy reduces tumor implantation and prolongs survival in a murine model of human pancreatic cancer

Matrix metalloproteinases (MMPs) participate in basement membrane degradati on, a critical step in invasion of cancer cells. We have previously shown t hat MMP inhibition of pancreatic cancers improves survival and decreases MM P production in vivo. The purpose of this study was to determine whether BB -94 was better than cytotoxic therapy and would increase the efficacy of cy totoxic therapy (gemcitabine) in a murine model of human pancreatic cancer. A human pancreatic adenocarcinoma cell line (HPAC) was injected into the p ancreata of BALB/c nu/nu mice. The mice were randomized 7 days after cancer cell injection to receive vehicle control, BB-94 gemcitabine, or gemcitabi ne and BB-94 until death or sacrifice at 84 days, At necropsy, tumors were harvested, and the relative enzyme activities of MMP-2 and MMP-9 were deter mined by gelatin zymography. Active MMP-2 levels in serum were determined u sing an ELISA technique. Combination treatment with gemcitabine and BB-94 s ignificantly reduced implantation rates and improved survival in mice with documented orthotopic tumors compared with either therapy alone or control. Tumor levels of active and latent MMP-2 were higher than those of MMP-9 in both treated and control mice. There was a significant reduction of tumor MMP-2 activity in mice treated with BB-94, gemcitabine, or gemcitabine and BB-94, Serum levels of active MMP-2 were reduced in all treated groups, wit h the greatest reduction occurring in mice treated with gemcitabine and BB- 94. Combination therapy with gemcitabine and BB-94 reduces cancer implantat ion and improves survival compared to treatment with BB-94, gemcitabine, or vehicle control alone. MMP production was reduced in all treated groups, r eflecting reduced tumor progression, which was particularly seen with combi nation therapy with gemcitabine and BB-94, This study supports combining MM P inhibition with cytotoxic therapy (gemcitabine) for patients with pancrea tic cancer.