Anti-angiogenic effect of 5-Fluorouracil-based drugs against human colon cancer xenografts
Anti-angiogenic effect of 5-Fluorouracil-based drugs against human colon cancer xenografts
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DOI：
10.1016/j.canlet.2008.03.008
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发表时间：
2008-08-18
期刊：
影响因子：
9.7
通讯作者：
Fukushima, Masakazu
中科院分区：
文献类型：
--
作者：
Ooyama, Akio;Oka, Toshinori;Fukushima, Masakazu
除了化疗药物对肿瘤细胞的直接细胞毒作用外，这些药物通过靶向肿瘤血管中增殖的内皮细胞而获得的抗血管生成活性也引起了很多研究兴趣。在这项研究中，我们检测了基于 5-氟尿嘧啶 (5-FU) 的药物（S-1 [1 M 替加氟、0.4 M 5-氯-2,4-二羟基吡啶和 1 M 氧酸钾] 和卡培他滨）对人结直肠癌异种移植物的抗肿瘤活性，并评估了它们的抗血管生成作用。两种药物在低于最大耐受剂量 (MTD) 的次最大耐受剂量 (sub-MTD) 下均表现出针对 COL-1 异种移植物的显着抗肿瘤活性。在低于 MTD 时，在用 S-1 处理的异种移植物中观察到微血管数量显着减少，肿瘤相关微血管内皮细胞凋亡增强。此外，我们发现，在亚MTD下接受S-1治疗的动物的异种移植肿瘤组织和血浆中，血小板反应蛋白-1（TSP-1）的表达（已知是节律化疗抗血管生成作用的介质）显着上调。卡培他滨也显示出诱导 TSP-1 的趋势。这些结果表明，基于 5-FU 的药物通过不同的作用模式抑制肿瘤进展，包括 5-FU 衍生的细胞毒活性和通过诱导 TSP-1 抑制血管生成。 (C) 2008 Elsevier Ireland Ltd. 保留所有权利。
In addition to the direct cytotoxic effects of chemotherapy agents on tumor cells, the anti-angiogenic activities attained by these agents by targeting proliferating endothelial cells in tumor blood vessels has attracted much research interest. In this study, we examined the antitumor activity of 5-Fluorouracil (5-FU)-based drugs (S-1 [1 M tegafur, 0.4 M 5-chloro-2,4-dihydroxypyridine and 1 M potassium oxonate] and capecitabine) on human colorectal cancer xenografts and evaluated their anti-angiogenic effects. Both drugs showed significant antitumor activities against COL-1 xenografts at a sub-maximum tolerated dose (sub-MTD), which was lower than the maximum tolerated dose (MTD). At the sub-MTD, a significant reduction in the microvessel number and the enhancement of tumor-associated microvessel endothelial cell apoptosis was seen in xenografts treated with S-1. In addition, we found that thrombospondin-1 (TSP-1) expression, known to be a mediator of the anti-angiogenic effects of metronomic chemotherapy, was significantly up-regulated in xenograft tumor tissues and plasma in animals treated with S-1 at a sub-MTD. Capecitabine also showed a trend toward the induction of TSP-1. These results suggest that 5-FU-based drugs inhibit tumor progression through different modes of action, including cytotoxic activity derived from 5-FU and the inhibition of angiogenesis through the induction of TSP-1. (C) 2008 Elsevier Ireland Ltd. All rights reserved.