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Integrin _vβ₃-Targeted Radioimmunotherapy of Glioblastoma Multiforme

Authors' Affiliations: ¹ Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program and Departments of ² Neurosurgery and ³ Pathology, Stanford University School of Medicine, Stanford, California; and ⁴ Medical Isotopes Research Center, Peking University, Beijing, China

Requests for reprints: Xiaoyuan Chen, Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, P095, Stanford, CA 94305-5484. Phone: 650-725-0950; Fax: 650-736-7925; E-mail: shawchen{at}stanford.edu or Fan Wang, Medical Isotopes Research Center, Peking University, 38#, Xueyuan Road, Beijing 100083, China. E-mail: wangfan{at}bjmu.edu.cn.

Purpose: Abegrin is a monoclonal antibody to human integrin _Vβ₃, 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 µCi 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.