title: Integrin alphavbeta3-targeted radioimmunotherapy of glioblastoma multiforme.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Radioimmunotherapy with 90Y-labeled Abegrin may prove promising in the treatment of highly vascular, invasive, and heterogeneous malignant brain tumors.
authors.affiliation: Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California 94305-5484, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Veeravagu
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Bing
authors.initials: B
authors.lastname: Jia
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
authors.forename: Cunjing
authors.initials: C
authors.lastname: Jin
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hsu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Connolly
authors.forename: Victor
authors.initials: V
authors.lastname: Tse
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D039302:Integrin alphaVbeta3 / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; C112567:etaracizumab