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。我们建立了一个小鼠“原发性肿瘤切除模型”，在该模型中，在原位移植结直肠癌组织后切除移植的肿瘤，以评估血管生成抑制剂对肝转移的治疗效果。从Scolecobasidium arenarium F-2015的发酵产物中分离并化学修饰的血管生成抑制剂FR-118487被分类为烟曲霉素家族的成员。在此，将FR-118487以1 mg/kg/天通过渗透泵皮下给予裸鼠1周、2周或4周，使用原位移植模型的实验结果显示，FR-118487显著抑制肿瘤生长和肝转移。9只对照小鼠中有7只出现肝转移，移植后2周接受肿瘤切除（早期切除）的6只小鼠中有2只出现肝转移，所有7只小鼠均出现肝转移。 ...更多信息 f移植后4周进行肿瘤切除的小鼠（晚期切除）。有趣的是，在所有接受肿瘤切除术的小鼠中均发生了腹膜播散。在短期治疗试验中，早期切除后立即给予FR-118487完全抑制了肝转移和腹膜转移，而晚期切除后给予FR-118487对肝转移没有影响，但显著抑制了腹膜扩散。在延长治疗试验中，明确证明了FR-118487延长治疗对晚期切除术后肝转移和腹膜转移的抑制作用。单纯切除组小鼠均在接种肿瘤后106天内死亡，原因为结肠癌肝转移和腹膜转移。相比之下，在观察期结束时（移植后160天），接受切除术并接受抗血管生成治疗的小鼠中有一半存活。因此，原发性肿瘤的肿块通过手术切除，残余的微小肿瘤通过抗血管生成治疗来控制。结论：手术联合抗血管生成治疗可能有助于预防大肠癌远处转移，改善大肠癌患者的预后。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