TSU68, an antiangiogenic receptor tyrosine kinase inhibitor, induces tumor vascular normalization in a human cancer xenograft nude mouse model
TSU68, an antiangiogenic receptor tyrosine kinase inhibitor, induces tumor vascular normalization in a human cancer xenograft nude mouse model
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DOI：
10.1007/s00595-009-4020-y
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发表时间：
2009-12-01
期刊：
影响因子：
2.5
通讯作者：
Konno, Hiroyuki
中科院分区：
文献类型：
--
作者：
Ohta, Manabu;Kawabata, Toshiki;Konno, Hiroyuki
使用抗血管生成药物和细胞毒药物联合治疗晚期癌症是一种有用的策略，但其机制尚未阐明。此外，有一个持续的悖论，即用抗血管生成药物破坏肿瘤血管会干扰细胞毒剂的输送。据推测，抗血管生成药物可以使结构和功能异常的肿瘤血管正常化。正常化意味着增加细胞毒剂的输送。我们的目的是研究针对血管内皮生长因子受体-2(VEGFR2)、血小板衍生生长因子受体(PDGFR)和成纤维细胞生长因子受体(FGFR)的多受体酪氨酸激酶抑制剂TSU68是否能诱导肿瘤血管正常化。在给药前后测量肿瘤间质液体压(IFP)。CD31和α-SMA免疫荧光双重染色，窄带照明医用视频内窥镜系统(NBI)显示血管形态，TSU68治疗显著降低IFP。免疫荧光双重染色显示TSU68处理组周细胞覆盖率明显增加。NBI内窥镜检查显示，经TSU68治疗的小鼠肿瘤血管大量被修剪，残留的血管管径缩小。这些数据支持我们的假设，即肿瘤血管在抗血管生成药物TSU68的作用下恢复正常。
Combination therapy using antiangiogenic and cytotoxic agents is a useful strategy for advanced cancer, but the mechanism has not yet been elucidated. Moreover, there is a persistent paradox that destroying tumor vasculature with antiangiogenic agents disturbs the delivery of cytotoxic agents. It has been hypothesized that antiangiogenic agents can lead to normalization of tumor vessels that are structurally and functionally abnormal. The normalization means enhancing the deliver of cytotoxic agents. Our purpose was to investigate whether TSU68, a multiple receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), would induce the normalization of tumor vessels.TSU68 was administered for 7 days to mice with xenografted tumors. Tumors of interstitial fluid pressure (IFP) were measured before and after administration of agents. Immunofluorescence double staining for CD31 and alpha-SMA was performed, and a medical video endoscopy system with narrowband illumination (NBI) was used to visualize the vascular pattern.TSU68 treatment decreased IFP significantly. Immunofluorescence double staining showed a significant increase in the fraction of pericyte coverage in the TSU68-treated group. NBI endoscopy showed that many tumor vessels in TSU68-treated mice were pruned and the diameters of remaining vessels were reduced.The data supported our hypothesis of tumor vascular normalization by the antiangiogenic agent TSU68.