Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat

Abstract

We have investigated the antitumor effects of synthetic MMP inhibitor MMI270 against postoperative lung metastasis from colon cancer in nude rat. The KM12SM human colon cancer cells were injected into the cecal wall, and at 5 weeks after the injection, the cecum was removed including the tumor. Then, 30 mg/kg of MMI270 was administered perorally twice per day for 2 or 4 weeks, either immediately after removal or after week 2 after the removal. At week 7 after the removal, lung metastasis was significantly inhibited by the early administration of MMI270 immediately after the tumor removal but not by the late administration. The survival rates were significantly higher in the rats treated by early administration of MMI270 compared to the survival rate in untreated rats. Moreover, no lung metastasis was detected in some rats with 24-weeks' survival treated by early administration. Lower microvessel density, lower PCNA Index and higher Apoptotic Index in the lung metastases of the rats treated with MMI270 were found compared to those in untreated rats. A beneficial effect of by early administration of MMI270 against postoperative lung metastases may be expected through inhibiting neovascularization of metastases in nude rat. ' 2005 Wiley-Liss, Inc.Key words: preclinical lung metastases model; angiogenesis; apoptosis; postoperative adjuvant therapy Colorectal cancer remains one of the major causes of cancer death worldwide. The mainstay of treatment for colorectal cancer with curative intent is surgical resection. However, recurrences to the liver or lung may occur in some patients even after a potentially curative operation. 1 For instance, the overall 5-year-survival rate for stage III cancer is approximately 60 % 2 due to postoperative recurrences even if the patients receive adjuvant chemotherapy. It is thought that the development of distant metastases depends on the spread of cancer cells from the primary tumor and that micrometastases already established prior to primary tumor resection appear as recurrent tumors after the operation. Therefore, to improve the postoperative prognosis of patients with colorectal cancer, effective adjuvant therapies against the micrometastases such as chemotherapy and immunotherapy should be considered. Since the 1990s, chemotherapy using 5-fluorouracil and leucovorin (5-FU/LV) has become standard treatment for stage III colon cancer after successful surgery. 3,4 However, this chemotherapy is still insufficient for patients at a high risk to recurrence who have biologically aggressive tumors, and the need to improve the outcome in such patients has increased the interest in developing more intensive or more targeted therapeutic strategies.It has been shown that solid tumor growth beyond a certain size requires neovascularization to supply the tumor with oxygen and nutrients. 5 In other words, without neovascularization, micrometastasis cannot grow. Therefore, it has been suggested that antiangiogenic therapy is effective against various solid tumors by inhibiting neovascularizat...

Chemokine receptor 7 enhances cell chemotaxis and migration of metastatic squamous cell carcinoma of head and neck through activation of matrix metalloproteinase-9

“…The expression of MMP-9 was enhanced in a variety of malignant tumors, cultured tumor cells and oncogene transformed cells. In vitro migration assay confirmed that the high invasive ability of tumor is associated with the high expression of MMP-9 (19)(20)(21).…”

Matrix metalloproteinases and tumor metastasis

“…Many novel MMP inhibitors effectively suppress neovascularization of tumors developing in experimental metastasis models. A synthetic MMP inhibitor (MMI270) administered early after postoperative primary tumor removal, demonstrated antitumor effects for lung metastases originating from colon cancer in nude rats [110]. Mechanistically, the findings confirmed that MMP inhibition diminishes neovascularization of metastases.…”

The Role of Matrix Metalloproteinases in Colorectal Cancer

“…This point is highlighted by the results of a study involving a synthetic MMPI, MMI270, in a rat model of colon cancer metastasis [46]. MMI270 competitively binds to zinc in the active state of several MMPs including MMP-1, -2, -3, -9 and -13 resulting in their inhibition.…”