Prevention of hepatic metastasis after surgery by angiogenesis inhibitor

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Hepatic metastasis after curative surgery is the most common type of recurrence of colorectal cancer. We established a mouse "primary tumor resection model" in which a transplanted tumor was resected after an orthotopic transplantation of colorectal cancer tissue to estimate the therapeutic effect of an angiogenesis inhibitor on liver metastasis. The angiogenesis inhibitor FR-118487, isolated from the fermentation products of Scolecobasidium arenarium F-2015 and modified chemically, was classified as a member of the fumagillin family. Here, one mg/kg/day of FR-118487 was subcutaneously administered to nude mice for one week, 2 weeks, or 4 weeks through an osmotic pump.The results of the experiment using the orthotopic transplantation model revealed that FR-118487 significantly inhibited the tumor growth and hepatic metastasis. Liver metastasis developed in 7 of 9 control mice, 2 of 6 mice that underwent the tumor resection 2 weeks after transplantation (early resection), and in all 7 o … More f the mice that underwent the tumor resection 4 weeks after transplantation (late resection). Interestingly, peritoneal dissemination developed in all of the mice that underwent a tumor resection. In the short treatment trial, the FR-118487 administration immediately after the early resection completely inhibited both hepatic and peritoneal metastasis, whereas its administration after the late resection had no effect on liver metastasis, but significantly inhibited the peritoneal dissemination. In the prolonged treatment trial, inhibitory effects of prolonged treatment with FR-118487 on both hepatic and peritoneal metastases after the late resection were clearly demonstrated. The mice of the resection-alone group all died within 106 days after tumor inoculation, due to hepatic and peritoneal metastases of colon carcinoma. In contrast, half of the mice that underwent resection and then received antiangiogenic therapy were alive at the end of the observational period (160 days after transplantation).Antiangiogenic therapy is more effective against microtumor than against a mass of tumor. Thus, a mass of primary tumor is removed by surgery and remnant microtumors are controlled by antiangiogenic therapy. In conclusion, the combination of surgery and subsequent antiangiogenic therapy may be useful to prevent the distant metastasis of colorectal cancer and improve the prognosis of patients with colorectal cancer. Less