Anti-angiogenic Therapy on Gastrointestinal Cancer

胃肠癌的抗血管生成治疗

• 批准号: 11671225
• 负责人: TANAKA Tatsuo
• 金额: $ 2.11万
• 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671225/
• 关键词: anti-angigenic therapy; human colon cancer; nude mouse model; liver metastasis; metalloproteinase inhibitor; ヌードマウスモデル; MMP阻害剤; 血管新生阻害; 大腸癌肝転移; ヒト大腸癌TK4; 大腸癌同所移植モデル

Several synthetic inhibitors of matrix metalloproteinases (MMPs) have been designed and have revealed anti-tumor, anti-metastasis and anti-angiogenesis effects in various models. Synergistic effects of the combination with conventional cytotoxic agents were reported previously. In this study, we cxamined the effects of a new selective MMP inhibitor, MMI-166, on tumor growth, angiogenesis and metastasis in a liver metastatic model of human xenotransplanted colon cancer (TK-4). We also investigated the synergistic effects of MMI-166 and a conventional cytotoxic agent, mitomycin C (MMC) in this model. Mice transplanted with TK-4 orthotopically were divided into 4 groups ; a control group (treated by vehicle solution), MMI-166 group in which MMI-166 was orally administered (p.o.) at a dose of 200mg/kg, 6days/week for 5 weeks, MMC group in which MMC was administered intraperitoneally (i.p.) at a dose of 2mg/kg/week for 5 weeks, and a combination group (treated by MMI-166 and MMC). MMI-166 did not inhibit transplanted tumor growth, but significantly inhibited liver metastasis compared with the control group and MMC group (P<0.01). Significant antitumor and antimetastatic effects were demonstrated by the combination therapy. The microvessel density (MVD) detected by immunohistochemical staining with ER-MP12 antibody had a tendency to be low in the MMI-166and the combination groups. These results suggest that MMI-166 has the potential anti-metastatic ability and a synergistic effect with MMC.

几种基质金属蛋白酶（MMP）的合成抑制剂已被设计出来，并在各种模型中显示出抗肿瘤、抗转移和抗血管生成作用。先前报道了与常规细胞毒剂组合的协同效应。在这项研究中，我们在人类异种移植结肠癌（TK-4）肝转移模型中检查了新型选择性 MMP 抑制剂 MMI-166 对肿瘤生长、血管生成和转移的影响。我们还在该模型中研究了 MMI-166 和传统细胞毒剂丝裂霉素 C (MMC) 的协同效应。原位移植TK-4的小鼠分为4组；对照组(用载体溶液处理)、MMI-166组(口服MMI-166以200mg/kg的剂量、6天/周、持续5周)、MMC组(其中MMC以2mg/kg/周的剂量腹膜内(i.p.)施用、持续5周)、以及联合组(用MMI-166和MMI-166治疗) MMC）。与对照组和MMC组相比，MMI-166不抑制移植瘤生长，但显着抑制肝转移（P<0.01）。联合治疗证明了显着的抗肿瘤和抗转移作用。通过ER-MP12抗体免疫组织化学染色检测到的微血管密度(MVD)在MMI-166和联合组中具有较低的趋势。这些结果表明MMI-166具有潜在的抗转移能力并与MMC具有协同作用。

项目成果

Tatsuo Tanaka, Hiroyuki Konno, et al.: "Prevention of hepatic and peritoneal metastases by the angiogenesis inhibitor FR-118487 after removal of growing tumor in mice"Japanese Journal of Cancer Research. 92(1). 88-94 (2001)

Tatsuo Tanaka、Hiroyuki Konno 等人：“血管生成抑制剂 FR-118487 在去除小鼠生长的肿瘤后预防肝和腹膜转移”《日本癌症研究杂志》。

田中達郎,今野弘之 他: "Prevention of hepatic and peritoneal metastases by the angiogenesis inhibitor FR-118487 after removal of growing tumor in mice"Japanese Journal of Cancer Research. 92・1. 88-94 (2001)

Tatsuro Tanaka、Hiroyuki Konno 等：“血管生成抑制剂 FR-118487 在去除小鼠生长的肿瘤后预防肝和腹膜转移”日本癌症研究杂志 92·1 (2001)。