IS20I, a specific alphavbeta3 integrin inhibitor, reduces glioma growth in vivo.
OBJECTIVE
The biological features of malignant gliomas include high cell proliferation, extensive local infiltration of tumor cells into normal brain, and marked neovascularization. alphavbeta3 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 alphavbeta3 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 alphavbeta3 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.


CONCLUSIONS
This work expands the understanding of the effects of anti-alphavbeta3 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.
Bello
Lorenzo
L
Division of Neurosurgery, Department of Neurological Sciences, University of Milan, Italy. lorenzo.bello@unimi.it
Lucini
Valeria
V
Giussani
Carlo
C
Carrabba
Giorgio
G
Pluderi
Mauro
M
Scaglione
Francesco
F
Tomei
Giustino
G
Villani
Roberto
R
Black
Peter McL
PM
Bikfalvi
Andreas
A
Carroll
Rona S
RS
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005910:Glioma / Q000473:pathology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology
D000970:Antineoplastic Agents; C472065:IS20I; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010456:Peptides, Cyclic