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Clin Cancer Res. 2008 Nov 15;14(22):7330-9. doi: 10.1158/1078-0432.CCR-08-0797.

Integrin alphavbeta3-targeted radioimmunotherapy of glioblastoma multiforme.

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  • 1Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California 94305-5484, USA.

Abstract

PURPOSE:

Abegrin is a monoclonal antibody to human integrin alphavbeta3, a cell adhesion molecule highly expressed on actively angiogenic endothelium and glioblastoma multiforme tumor cells. The purpose of this study was to evaluate the efficacy of a novel 90Y-Abegrin radioimmunotherapeutic agent in murine xenograft glioblastoma models with noninvasive in vivo molecular imaging modalities.

EXPERIMENTAL DESIGN:

A s.c. U87MG human glioblastoma xenograft model was used to determine maximum tolerated dose (MTD), biodistribution, dose response, and efficacy of 90Y-Abegrin. Antitumor efficacy was also characterized in an orthotopic U87MG and in a HT-29 colorectal cancer model, a low integrin-expressing carcinoma. Small-animal positron emission tomography imaging was used to correlate histologic findings of treatment efficacy.

RESULTS:

MTD and dose response analysis revealed 200 microCi per mouse as appropriate treatment dose with hepatic clearance and no organ toxicity. 90Y-Abegrin-treated U87MG tumor mice showed partial regression of tumor volume, with increased tumor volumes in 90Y-IgG, Abegrin, and saline groups. 18F-FDG imaging revealed a reduction of cell proliferation and metabolic activity whereas 18F-FLT reflected decreased DNA synthesis in the 90Y-Abegrin group. Ki67 analysis showed reduced proliferative index and quantitative terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive analysis revealed increased DNA fragmentation and apoptosis in 90Y-Abegrin animals. CD31 and 4',6-diamidino-2-phenylindole staining showed increased vascular fragmentation and dysmorphic vessel structure in 90Y-Abegrin animals only. Orthotopic U87MG tumors treated with 90Y-Abegrin displayed reduced tumor volume. HT-29 tumors showed no significant difference among the various groups.

CONCLUSION:

Radioimmunotherapy with 90Y-labeled Abegrin may prove promising in the treatment of highly vascular, invasive, and heterogeneous malignant brain tumors.

PMID:
19010848
[PubMed - indexed for MEDLINE]
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