Matrix metalloproteinases (
MMPs) participate in basement membrane degradation, a critical step in invasion of
cancer cells. We have previously shown that
MMP inhibition of
pancreatic cancers improves survival and decreases
MMP 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 cytotoxic
therapy (
gemcitabine) in a murine model of human
pancreatic cancer. A human pancreatic
adenocarcinoma cell line (HPAC) was injected into the pancreata of BALB/c nu/nu mice. The mice were randomized 7 days after
cancer cell injection to receive vehicle control,
BB-94,
gemcitabine, or
gemcitabine 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 determined by
gelatin zymography. Active MMP-2 levels in serum were determined using an ELISA technique. Combination treatment with
gemcitabine and
BB-94 significantly 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, with the greatest reduction occurring in mice treated with
gemcitabine and
BB-94. Combination
therapy with
gemcitabine and
BB-94 reduces
cancer implantation and improves survival compared to treatment with
BB-94,
gemcitabine, or vehicle control alone.
MMP production was reduced in all treated groups, reflecting reduced
tumor progression, which was particularly seen with combination
therapy with
gemcitabine and
BB-94. This study supports combining
MMP inhibition with cytotoxic
therapy (
gemcitabine) for patients with
pancreatic cancer.