IS20I, a specific αvβ3 integrin inhibitor, reduces glioma growth in vivo

Lorenzo Bello, Valeria Lucini, Carlo Giussani, Giorgio Carrabba, Mauro Pluderi, Francesco Scaglione, Giustino Tomei, Roberto Villani, Peter Mc L Black, Andreas Bikfalvi, Rona S. Carroll, Berislav Zlokovic, Joseph M. Piepmeier, Roberta Glick, Terry Lichtor

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE: The biological features of malignant gliomas include high cell proliferation, extensive local infiltration of tumor cells into normal brain, and marked neovascularization. αvβ3 integrin is highly expressed in malignant gliomas and plays a role in glioma growth. This article investigates the in vitro and in vivo effects of a synthetic αvβ3 integrin inhibitor called IS20I on human malignant gliomas. METHODS: The in vitro effects of IS20I were studied by performing adhesion assays, competition studies, semi-in vivo angiogenic assays, and migration and proliferation assays. For the in vivo experiments, IS20I was administered systemically in nude mouse intracranial and subcutaneous malignant glioma models. RESULTS: IS20I reacted selectively to αvβ3 integrin in glioma cells and tissues. In vitro, IS20I strongly inhibited angiogenesis and simultaneously exhibited potent antimitotic and antimigratory effects on numerous tumor and endothelial cell lines. In addition, at high concentrations, IS20I induced endothelial and tumor cell apoptosis. In vivo, when IS20I was administered intraperitoneally in subcutaneous and intracranial nude mouse glioma models, it potently reduced malignant glioma growth. Inhibition levels of 76 and 82% were observed at concentrations of 1 and 5 mg/kg, respectively, in the U87 intracranial model. The suppression of tumor growth is associated with a decrease in tumor vascularity, an increase in apoptosis, and a decrease in tumor cell proliferation. CONCLUSION: This work expands the understanding of the effects of anti-αvβ3 integrin inhibitors on malignant gliomas. In addition to direct proapoptotic and antiangiogenic effects, IS20I inhibits tumor and endothelial cell proliferation and migration, resulting in a potent inhibition of glioma growth in vivo.

Original languageEnglish
Pages (from-to)177-186
Number of pages10
JournalNeurosurgery
Volume52
Issue number1
DOIs
Publication statusPublished - Jan 1 2003

Keywords

  • Angiogenesis
  • Glioma
  • IS20I
  • Migration
  • Proliferation

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

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