Effect of combination therapy with matrix metalloproteinase inhibitor MMI-166 and mitomycin C on the growth and liver metastasis of human colon cancer

Several synthetic inhibitors of matrix metalloproteinases (MMPs) show antit umor, antimetastasis and antiangiogenesis effects in various models, Synerg istic effects of combinations with conventional cytotoxic agents were repor ted previously. In this study, we examined the effects of a new selective M MP inhibitor, MMI-166, on tumor growth, angiogenesis and metastasis in a li ver metastatic model of human xenotransplanted colon cancer (TK-4). We also investigated the synergistic effects of MMI-166 and a conventional cytotox ic agent, mitomycin C (MMC), in this model, Mice transplanted orthotopicall y with TK-4 were divided into 4 groups; a control group (treated with vehic le 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 MMIC group in which MMC was administered intraperitoneally (i.p.) at a dose of 2 mg/kg/week fo r 5 weeks, and a combination group (treated with MMI-166 and MMC). MMI-166 did not inhibit transplanted tumor growth, but significantly inhibited live r metastasis compared with the control group and MMC group (P < 0.01). Sign ificant antitumor and antimetastatic effects of the combination therapy wer e demonstrated, The microvessel density (MVD) detected by immunohistochemic al staining with ER-MP12 antibody tended to be loner in the MMI-166 and the combination groups, These results suggest that MMI-166 has potential antim etastatic ability and a synergistic effect with MMC.