Prevention of hepatic metastasis after surgery by angiogenesis inhibitor

血管生成抑制剂预防术后肝转移

基本信息

批准号：
10671171
负责人：
NAKAMURA Toshio
金额：
$ 1.98万
依托单位：
Hamamatsu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671171/
关键词：
Antiangiogenesis inhibitor Human colon cancer Metastasis after surgery Hepatic metastasis TK 4 Removal of tumor 大腸癌術後転移 FR-118487 ヒト大腸癌TK4 大腸癌原発巣切除モデル血管新生抑制 FR118487

项目摘要

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

治愈手术后的肝转移是结直肠癌的最常见类型。我们建立了一个小鼠“原发性肿瘤切除模型”，其中在直接移植结直肠癌组织后切除了移植的肿瘤，以估计血管生成抑制剂对肝转移的治疗作用。从Scolecobasidium artharium F-2015和化学修饰的发酵产物中分离出的血管生成抑制剂FR-118487被归类为富马吉林家族的成员。在此，通过渗透泵通过皮下对裸鼠的1 mg/kg/天皮下给予裸鼠一周，2周或4周。使用原位移植模型，实验的结果表明，FR-118487显着抑制了肿瘤生长和hepatitic the肿瘤的生长。肝转移在9名对照小鼠中有7只，在移植后2周接受肿瘤切除的6只小鼠中的2个（早期切除术），在所有7 O中，在移植后4周（晚切除术）4周下的所有7 O…更多。有趣的是，在肿瘤切除术下的所有小鼠中都发展了腹膜传播。在简短的治疗试验中，早期切除后立即进行FR-118487给药，完全抑制了肝和腹膜转移，而后期切除后的给药对肝转移没有影响，但显着抑制了腹膜的传播。在一项长时间的治疗试验中，清楚地证明了晚期切除后肝脏和腹膜转移的延长治疗对肝和腹膜转移的抑制作用。肿瘤接种后106天，由于结肠癌的肝和腹膜转移，全部切除组的小鼠全部死亡。相反，在观察期结束时（移植后160天），一半接受切除并接受抗血管生成疗法的小鼠还活着。抗二亲疗法对微肿瘤的有效性比针对肿瘤的肿块更有效。这是通过手术去除大量原发性肿瘤，残留的微肿由抗血管生成疗法控制。总之，手术和随后的抗血管生成疗法的结合可能有助于防止结直肠癌的遥远转移并改善结直肠癌患者的预后。较少的