The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors
The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors
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DOI：
10.1007/s12032-021-01503-z
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发表时间：
2021-06-01
期刊：
影响因子：
3.4
通讯作者：
Gonda, Kohsuke
中科院分区：
文献类型：
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作者：
Une, Norikazu;Takano-Kasuya, Mayumi;Gonda, Kohsuke
血管生成抑制剂的评价需要对肿瘤血管的精确结构和功能进行分析。抗血管生成药物lenvatinib和sorafenib是已被批准用于治疗肝细胞癌的多靶点酪氨酸激酶抑制剂。然而，Lenvatinib和Sorafenib对肿瘤血管的不同影响还不是很清楚。在这项研究中，我们分析了两种药物对血管结构和功能的影响，包括血管正常化，并利用以纳米金为造影剂的微型X射线计算机断层扫描，免疫组织化学分析和间质液体压力(IFP)测量，研究正常化是否对药物和放射治疗的联合治疗有积极作用。在皮下移植小鼠肝癌细胞的小鼠中，用lenvatinib或sorafenib治疗14天可抑制肿瘤生长并降低肿瘤血管体积密度。然而，对药物治疗4天后测得的血管密度、周细胞覆盖率和灌注率、肿瘤缺氧和IFP的综合数据分析显示，与50 mg/kg索拉非尼治疗组相比，3 mg/kg lenvatinib组的微血管密度和归一化肿瘤血管显著减少。这些结果表明，比索拉非尼更早和更有效地诱导肝癌血管正常化和改善瘤内微环境。此外，这些变化增加了肿瘤的放射敏感性，并增强了伦瓦替尼和放射联合治疗的效果，表明该联合治疗在抗肝癌方面具有潜在的应用前景。
The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study, we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial fluid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib significantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib. Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.