Anti-angiogenic effects of SN38 (active metabolite of irinotecan): inhibition of hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells

  • Hiroshi Kamiyama
  • Shingo Takano
  • Koji Tsuboi
  • Akira Matsumura
Original Paper

Abstract

Purpose

Inhibition of angiogenesis is an important new treatment modality for malignancies, including gliomas. Vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α) have been investigated as potent mediators of tumor angiogenesis. We investigated whether four major chemotherapeutic agents (ACNU, cisplatin, etoposide, and SN38) showed an angiosuppressive effect in vitro.

Method

The effects of ACNU, cisplatin, etoposide, and SN38 for endothelial cells were assessed by cell growth inhibition assay (WST-8 assay) and vessel formation assay (angiogenesis kit). The inhibitory effects of the HIF-1α and VEGF expression of glioma cells after SN38 treatment were assessed by real-time RT-PCR, Western blot, and ELISA.

Results

SN38, but not other chemotherapeutic agents, selectively inhibited endothelial cell proliferation and three-dimensional tube formations at the 0.01 μM. Furthermore, SN38 significantly decreased the HIF-1α and VEGF expression of glioma cells in a dose- and time-dependent manner under normoxic and hypoxic conditions. SN38 has dual angiosuppressive actions, including both the inhibition of endothelial proliferation and tube formation, and the inhibition of the angiogenic cascade in glioma cells.

Conclusion

SN38 is an attractive agent as both a direct and indirect angiogenesis inhibitor and provides the anti-glioma agents with an angiosuppressive function.

Keywords

SN38 Irinotecan HIF-1α VEGF Angiogenesis inhibitor 

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Hiroshi Kamiyama
    • 1
  • Shingo Takano
    • 1
  • Koji Tsuboi
    • 1
  • Akira Matsumura
    • 1
  1. 1.Department of Neurosurgery, Institute of Clinical Medicine, Graduate School of Comprehensive Human SciencesUniversity of TsukubaTsukuba CityJapan

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