Effect of Combination Therapy with Matrix Metalloproteinase Inhibitor MMI-166 and Mitomycin C on the Growth and Liver Metastasis of Human Colon Cancer

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Abstract
Several synthetic inhibitors of matrix metalloproteinases (MMPs) show antitumor, antimetastasis and antiangiogenesis effects in various models. Synergistic effects of combinations with conventional cytotoxic agents were reported previously. In this study, we examined the effects of a new selective MMP inhibitor, MMI‐166, on tumor growth, angiogenesis and metastasis in a liver meta‐static model of human xenotransplanted colon cancer (TK‐4). We also investigated the synergistic effects of MMI‐166 and a conventional cytotoxic agent, mitomycin C (MMC), in this model. Mice transplanted orthotopically with TK‐4 were divided into 4 groups; a control group (treated with vehicle solution), an MMI‐166 group in which MMI‐166 was orally administered (p.o.) at a dose of 200 mg/kg, 6 days/week for 5 weeks, an MMC group in which MMC was administered intraperitoneally (i.p.) at a dose of 2 mg/kg/week for 5 weeks, and a combination group (treated with MMI‐166 and MMC). MMI‐166 did not inhibit transplanted tumor growth, but significantly inhibited liver metastasis compared with the control group and MMC group (P<0.01). Significant antitumor and antimetastatic effects of the combination therapy were demonstrated. The microvessel density (MVD) detected by immunohistochemical staining with ER‐MP12 antibody tended to be lower in the MMI‐166 and the combination groups. These results suggest that MMI‐166 has potential antimetastatic ability and a synergistic effect with MMC.

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