Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency.
We investigated whether cilengitide could amplify the antitumor effects of radiotherapy in an orthotopic rat glioma xenograft model. Cilengitide is a specific inhibitor of alphav series integrins, and acts as an antiangiogenic. U251 human glioma cells express alphavbeta3 and alphavbeta5 integrins. We used in vitro assays of adhesion and growth of tumor and endothelial cells to evaluate cytotoxicity and the potential for cilengitide to enhance radiation toxicity. Treatment was then evaluated in an orthotopic model to evaluate synergy with therapeutic radiation in vivo. In vitro, cilengitide blocked cell adhesion, but did not influence the effects of radiation on U251 cells; cilengitide strongly amplified radiation effects on endothelial cell survival. In vivo, radiotherapy prolonged the survival of U251 tumor-bearing rats from 50 to over 110 days. Cotreatment with cilengitide and radiation dramatically amplified the effects of radiation, producing survival over 200 days and triggering an enhanced apoptotic response and suppression of tumor growth by histology at necropsy. Signaling pathways activated in the tumor included NFkappab, a documented mediator of cellular response to radiation. Because cilengitide has a short plasma half-life (t((1/2)) approximately 20 min), antiangiogenic scheduling typically uses daily injections. We found that a single dose of cilengitide (4 mg/kg) given between 4 and 12 hr prior to radiation was sufficient to produce the same effect. Our results demonstrate that blockade of alphav integrins mediates an unanticipated rapid potentiation of radiation, and suggests possible clinical translation for glioma therapy.
Mikkelsen
Tom
T
Department of Neurosurgery, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI 48202, USA. nstom@neuro.hfh.edu
Brodie
Chaya
C
Finniss
Susan
S
Berens
Michael E
ME
Rennert
Jessica L
JL
Nelson
Kevin
K
Lemke
Nancy
N
Brown
Stephen L
SL
Hahn
Diane
D
Neuteboom
Berend
B
Goodman
Simon L
SL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002448:Cell Adhesion / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000528:radiation effects; D005909:Glioblastoma / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000032:analysis / Q000037:antagonists & inhibitors*; D020411:Oligonucleotide Array Sequence Analysis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019030:Receptors, Vitronectin / Q000032:analysis / Q000037:antagonists & inhibitors*; D012910:Snake Venoms / Q000493:pharmacokinetics / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D039302:Integrin alphaVbeta3; D011838:Radiation-Sensitizing Agents; D019030:Receptors, Vitronectin; D012910:Snake Venoms; D051996:Transcription Factor RelA; C064660:integrin alphaVbeta5; C422910:Cilengitide