title: Does imaging αvβ3 integrin expression with PET detect changes in angiogenesis during bevacizumab therapy?
abstract: In recent years, there has been a growing interest in molecular imaging markers of tumor-induced angiogenesis. Several radiolabeled RGD (arginine, glycine, aspartate) peptides have been developed for PET imaging of αvβ3 integrins in the tumor vasculature, but there are only limited data on how angiogenesis inhibitors affect the tumor uptake of these peptides.
  
  
  METHODS
  Changes in (68)Ga-NODAGA-c(RGDfK) peptide uptake were measured using PET during bevacizumab therapy of 2 αvβ3-negative squamous cell carcinoma cell lines (A-431 and FaDu) that induce αvβ3-positive neovasculature when transplanted into nude mice. Tumor uptake of (68)Ga-NODAGA-c(RGDfK) was correlated to microvascular density, vascular morphology, and permeability as well as αvβ3 integrin expression.
  
  
  RESULTS
  Bevacizumab significantly inhibited growth of A-431 tumors and caused a significant reduction in microvascular density and αvβ3 integrin expression within 7 d after start of therapy. Bevacizumab also caused a normalization of blood vessel morphology and decreased tumor necrosis. However, (68)Ga-NODAGA-c(RGDfK) uptake was significantly increased at day 7 of therapy and did not decrease until after 3 wk of treatment. In Fadu xenografts, bevacizumab therapy caused only a minor inhibition of tumor growth and minor changes in (68)Ga-NODAGA-c(RGDfK) uptake.
  
  
  CONCLUSIONS
  Uptake of radiolabeled RGD peptides is not necessarily decreased by effective antiangiogenic therapy. Early in the course of therapy a decrease in the expression of αvβ3 integrins may not be reflected by a decrease in the uptake of RGD peptides.
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany Department of Nuclear Medicine, University Medical Center, Freiburg, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany svetlana.rylova@uniklinik-freiburg.de.
authors.forename: Svetlana N
authors.initials: SN
authors.lastname: Rylova
authors.affiliation: Department of Pathology, University Medical Center, Freiburg, Germany.
authors.forename: Enikö
authors.initials: E
authors.lastname: Barnucz
authors.affiliation: Department of Nuclear Medicine, University Medical Center, Freiburg, Germany.
authors.forename: Melpomeni
authors.initials: M
authors.lastname: Fani
authors.affiliation: Department of Nuclear Medicine, University Medical Center, Freiburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Braun
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pathology, University Medical Center, Freiburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pathology, University Medical Center, Freiburg, Germany BIOSS Center for Biological Signaling Studies, Freiburg, Germany; and.
authors.forename: Silke
authors.initials: S
authors.lastname: Lassmann
authors.affiliation: Department of Nuclear Medicine, University Medical Center, Freiburg, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
authors.affiliation: Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Weber
mesh_terms: D000085:Acetates; D000465:Algorithms; D020533:Angiogenesis Inhibitors / Q000737:chemistry; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000068258:Bevacizumab; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005260:Female; D005710:Gallium Radioisotopes / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008833:Microcirculation; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D010539:Permeability; D049268:Positron-Emission Tomography; D013997:Time Factors
chemical_list: C572723:1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane; D000085:Acetates; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010455:Peptides; D000068258:Bevacizumab; C047981:arginyl-glycyl-aspartic acid
keywords: PET; angiogenesis; bevacizumab; normalization; αvβ3 integrin