The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors

Norikazu Une, Mayumi Takano-Kasuya, Narufumi Kitamura, Mineto Ohta, Tomoya Inose, Chihiro Kato, Ryuichi Nishimura, Hiroshi Tada, Shigehito Miyagi, Takanori Ishida, Michiaki Unno, Takashi Kamei, Kohsuke Gonda

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number60
JournalMedical Oncology
Volume38
Issue number6
DOIs
Publication statusPublished - 2021 Jun

Keywords

  • Computed tomography
  • Hepatocellular carcinoma
  • Lenvatinib
  • Radiation therapy
  • Sorafenib
  • Vascular normalization

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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