Anti-angiogenic Therapy on Gastrointestinal Cancer

已经设计了几种合成的基质金属蛋白酶抑制剂，并在各种模型中显示出抗肿瘤、抗转移和抗血管生成的作用。与常规细胞毒药物联合的协同效应先前有报道。在这项研究中，我们研究了一种新的选择性MMP抑制剂MMI-166对人类异种移植结肠癌（TK-4）肝转移模型中肿瘤生长、血管生成和转移的影响。我们还在该模型中研究了MMI-166和常规细胞毒性药物丝裂霉素C （MMC）的协同作用。TK-4原位移植小鼠分为4组；MMI-166组，MMI-166按200mg/kg剂量口服（p.o）， 6天/周，连续5周；MMC组，MMC按2mg/kg/周腹腔（i.p）给药，连续5周；MMI-166和MMC联合治疗组。与对照组和MMC组比较，MMI-166不抑制移植瘤生长，但显著抑制肝转移（P<0.01）。联合治疗具有显著的抗肿瘤和抗转移作用。ER-MP12抗体免疫组化染色检测微血管密度（MVD）在mmi -166和联合用药组有降低的趋势。这些结果表明MMI-166具有潜在的抗转移能力，并与MMC具有协同作用。

Several synthetic inhibitors of matrix metalloproteinases (MMPs) have been designed and have revealed anti-tumor, anti-metastasis and anti-angiogenesis effects in various models. Synergistic effects of the combination with conventional cytotoxic agents were reported previously. In this study, we cxamined the effects of a new selective MMP inhibitor, MMI-166, on tumor growth, angiogenesis and metastasis in a liver metastatic 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 with TK-4 orthotopically were divided into 4 groups ; a control group (treated by vehicle solution), MMI-166 group in which MMI-166 was orally administered (p.o.) at a dose of 200mg/kg, 6days/week for 5 weeks, MMC group in which MMC was administered intraperitoneally (i.p.) at a dose of 2mg/kg/week for 5 weeks, and a combination group (treated by 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 were demonstrated by the combination therapy. The microvessel density (MVD) detected by immunohistochemical staining with ER-MP12 antibody had a tendency to be low in the MMI-166and the combination groups. These results suggest that MMI-166 has the potential anti-metastatic ability and a synergistic effect with MMC.