gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor
gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor
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DOI：
10.1023/a:1014059528046
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发表时间：
2001-01-01
期刊：
影响因子：
9.8
通讯作者：
Yamada, Yuji
中科院分区：
文献类型：
--
作者：
Basaki, Yuji;Chikahisa, Lumi;Yamada, Yuji
UFT是一种由尿嘧啶和替加氟摩尔比为4:1的药物，是一种口服活性药物，用于治疗多种恶性肿瘤。通过小鼠背气囊（DAS）实验，我们已经证明UFT及其代谢物γ -羟基丁酸（GHB）和5-氟尿嘧啶（5-FU）抑制小鼠肾细胞癌诱导的血管生成。在这里，我们报告了UFT比其他氟化嘧啶如5- fu和多西氟啶（5'-DFUR）更有效地阻断五种人类癌细胞系引起的血管生成反应，这些癌细胞系产生高水平的血管内皮生长因子（VEGF），但在体外没有检测到成纤维细胞生长因子-2 （FGF-2）。相比之下，UFT无法阻断一种体外同时产生VEGF和FGF-2的人胃癌细胞系的血管生成反应。然而，这些细胞产生或分泌VEGF不受GHB和5-FU处理的影响。有趣的是，GHB抑制了受VEGF刺激的人脐静脉内皮细胞（HUVECs）的趋化迁移和管状形成，而不抑制其DNA合成。由于GHB不影响huvec中fgf -2驱动的活性，其作用似乎是vegf选择性的。另一方面，5-FU抑制了VEGF和FGF-2刺激的HUVECs的DNA合成和迁移，以及VEGF驱动的管形成，提示5-FU对内皮细胞具有细胞毒性。DAS法在体内重现了5-FU的抑制作用，特别是GHB的抑制作用。UFT、5-FU明显抑制vegf介导的血管生成，GHB尤其明显。我们认为GHB对vegf介导的内皮细胞反应的选择性抑制作用参与了UFT的抗血管生成活性。
UFT, a drug composed of uracil and tegafur at the molar ratio of 4:1, is an orally active agent for the treatment of a wide variety of malignant tumours. Using a murine dorsal air sac (DAS) assay, we have previously shown that UFT and its metabolites, gamma-hydroxybutyric acid (GHB) and 5-fluorouracil (5-FU), inhibited the angiogenesis induced by murine renal cell carcinoma. Here we report that UFT was more effective than other fluorinated pyrimidines such as 5-FU and doxifluridine (5'-DFUR) in blocking the angiogenic responses elicited by five human cancer cell lines which produced high levels of vascular endothelial growth factor (VEGF), but no detectable fibroblast growth factor-2 (FGF-2) in vitro. In contrast, UFT was unable to block the angiogenic response to one human gastric cancer cell line which produced both VEGF and FGF-2 in vitro. However, the production or secretion of VEGF by these cells was unaffected by GHB and 5-FU treatment. Interestingly, GHB suppressed the chemotactic migration and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by VEGF, without inhibiting their DNA synthesis. Since GHB did not affect the FGF-2-driven activities in HUVECs, its action appears to be VEGF-selective. On the other hand, 5-FU inhibited DNA synthesis and migration of HUVECs stimulated by both VEGF and FGF-2, and tube formation driven by VEGF, suggesting that 5-FU is cytotoxic to endothelial cells. The inhibitory effects of 5-FU, and especially those GHB, were reproduced under in vivo condition using the DAS assay. The VEGF-mediated angiogenesis was significantly inhibited by UFT, 5-FU, and especially by GHB. We propose that the selective inhibitory effects of GHB on VEGF-mediated responses of endothelial cells are involved in the anti-angiogenic activity of UFT.