Prevention of hepatic metastasis after surgery by angiogenesis inhibitor

根治性手术后肝转移是结直肠癌最常见的复发类型。我们建立了一种小鼠“初次肿瘤切除模型”，在该模型中，移植的肿瘤在结直肠癌组织原位移植后被切除，以评估血管生成抑制剂对肝转移的治疗效果。血管生成抑制因子FR-118487是从弧菌Scolecobasidium arenarium F-2015的发酵产物中分离得到的一种血管生成抑制物，经化学修饰后，属于烟青素家族成员。通过渗透压泵给裸鼠皮下注射FR-118487 1 mg/kg/d，分别持续1周、2周和4周。原位移植模型实验结果表明，FR-118487显著抑制肿瘤生长和肝转移。在9只对照小鼠中有7只发生了肝转移，在移植后2周(早期切除)接受肿瘤切除的6只小鼠中有2只发生了肝转移，所有7只…小鼠都发生了肝转移。更多的小鼠在移植后4周接受肿瘤切除(晚期切除)。有趣的是，所有接受肿瘤切除的小鼠都出现了腹膜播散。在短期治疗试验中，早期切除后立即给药的FR-118487完全抑制了肝和腹膜转移，而晚期切除后给药对肝转移无影响，但显著抑制了腹膜转移。在延长的治疗试验中，FR-118487的延长治疗对晚期切除后的肝和腹膜转移的抑制作用明显。单纯切除组小鼠均于接种肿瘤后106d内因结肠癌肝、腹膜转移而死亡。相比之下，接受切除然后接受抗血管生成治疗的小鼠中，有一半在观察期结束时(移植后160天)还活着。抗血管生成治疗对微小肿瘤比对大量肿瘤更有效。因此，大量的原发肿瘤可以通过手术切除，残留的微小肿瘤可以通过抗血管生成治疗来控制。结论：手术结合后续抗血管生成治疗可能有助于预防结直肠癌的远处转移，改善结直肠癌患者的预后。较少

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