The integrin inhibitor cilengitide affects meningioma cell motility and invasion.
OBJECTIVE
Meningiomas are frequent intracranial or spinal neoplasms, which recur frequently and can show aggressive clinical behaviour. We elucidated the impact of the integrin inhibitor cilengitide on migration, proliferation, and radiosensitization of meningioma cells.


METHODS
We analyzed integrin expression in tissue microarrays of human meningiomas and the antimeningioma properties of cilengitide in cell cultures, subcutaneous and intracranial nude mouse models by measuring tumor volumes and survival times.


RESULTS
αvβ5 was the predominantly expressed integrin heterodimer in meningiomas, whereas αvβ3 was mainly detected in tumor blood vessels. Application of up to 100 μg/mL cilengitide resulted in only mildly reduced proliferation/survival of meningioma cell lines. Effects on cell survival could be enhanced by irradiation. One μg/mL cilengitide was sufficient to significantly inhibit meningioma cell migration and invasion in vitro. A daily dosage of 75 mg/kg did neither affect tumor volumes nor overall survival (P = 0.813, log-rank test), but suppressed brain invasion in a significant fraction of treated animals. A combination of 75 mg/kg cilengitide daily and irradiation (2 × 5 Gy) led to a 67% reduction of MRI-estimated tumor volumes in the intracranial model (P < 0.01), whereas the corresponding reduction reached by irradiation alone was only 55% (P < 0.05).


CONCLUSIONS
These data show that a monotherapy with cilengitide is not likely to achieve major responses in rapidly growing malignant meningiomas, although brain invasion may be reduced because of the strong antimigratory properties of the drug. The combination with radiotherapy warrants further attention.
Authors' Affiliations: Departments of Neuropathology, Neurosurgery and Radiotherapy, Otto vonGuericke University; Neurosurgery, City Hospital; Special Lab for Non-Invasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg; Neurosurgery, Paracelsus Hospital, Zwickau; and Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.
Annette
A
Wilisch-Neumann
Nadine
N
Kliese
Doreen
D
Pachow
Thomas
T
Schneider
Jan-Peter
JP
Warnke
Werner Ek
WE
Braunsdorf
Frank-Dietmar
FD
Böhmer
Peter
P
Hass
Diana
D
Pasemann
Cornelia
C
Helbing
Elmar
E
Kirches
Christian
C
Mawrin
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008577:Meningeal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy; D008579:Meningioma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy; D051379:Mice; D009361:Neoplasm Invasiveness; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D012910:Snake Venoms / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects
D016023:Integrins; D025581:Neurofibromin 2; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C064660:integrin alphaVbeta5; C422910:Cilengitide