Matrix metalloproteinase inhibition improves survival in an orthotopic model of human pancreatic cancer

Matrix metalloproteinases (MMPs) have been implicated in the growth and inv asiveness of primary and metastatic tumors. Hypothesizing that MMP inhibiti on would slow cancer growth, the MMP inhibitor BE-94 (batimistat) was evalu ated in an orthotopic animal model of human pancreatic carcinoma. Ten milli on human pancreatic cancer cells were surgically implanted into the pancrea ta of 30 athymic nu/nu mice. Intraperitoneal administration of 30 mg/kg BE- 94 or vehicle control began 7 days after turner implantation (13 mice with confirmed implantations in each group) and continued daily fur 21 days, and then three times weekly until death or sacrifice at day 70. Representative tumors harvested from twice in each group were analyzed for presence and a ctivity of MMP-2 and MMP-9. Animal weights w ere significantly higher in ti le BB-94-treated group at sacrifice (mean 58.4 +/- 7.9 g vs. 39.8 +/- 6.2 g ; P <0.05, Student's t test). The likelihood of survival to 70 days was sig nificantly higher in the treated group (4 of 13 vs. 0 of 13, P <0.05, Z-tes t for end points) than in the control group as was overall survival (P = 0. 03, Wilcoxon test). Nine mice in the control group developed metastases tu the liver, peritoneum, abdominal wall, or local lymph nodes, whereas only t wo mice in the BB-94 group had evidence of metastatic disease (P <0.02, Fis her's exact test), in both instances confined to the abdominal wall. Tumors from treated mice manifested lower MMP activity than those from control an imals. These reports support the use of MMP inhibitors alone or as an adjun ct in the treatment of pancreatic cancer.