Svetlana N Rylova1, Enikö Barnucz2, Melpomeni Fani3, Friederike Braun3, Martin Werner4, Silke Lassmann5, Helmut R Maecke3, Wolfgang A Weber6. 1. 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. 2. Department of Pathology, University Medical Center, Freiburg, Germany. 3. Department of Nuclear Medicine, University Medical Center, Freiburg, Germany. 4. German Cancer Consortium (DKTK), Heidelberg, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pathology, University Medical Center, Freiburg, Germany. 5. 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. 6. Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract
UNLABELLED: 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. CONCLUSION: 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.
UNLABELLED: 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. CONCLUSION: 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: Riikka Siitonen; Emilia Peuhu; Anu Autio; Heidi Liljenbäck; Elina Mattila; Olli Metsälä; Meeri Käkelä; Tiina Saanijoki; Ingrid Dijkgraaf; Sirpa Jalkanen; Johanna Ivaska; Anne Roivainen Journal: J Nucl Med Date: 2019-03-08 Impact factor: 10.057
Authors: Monique R Bernsen; Klazina Kooiman; Marcel Segbers; Fijs W B van Leeuwen; Marion de Jong Journal: Eur J Nucl Med Mol Imaging Date: 2015-02-12 Impact factor: 9.236
Authors: Philipp M Kazmierczak; Andrei Todica; Franz-Josef Gildehaus; Heidrun Hirner-Eppeneder; Matthias Brendel; Ralf S Eschbach; Magdalena Hellmann; Konstantin Nikolaou; Maximilian F Reiser; Hans-Jürgen Wester; Saskia Kropf; Axel Rominger; Clemens C Cyran Journal: PLoS One Date: 2016-12-19 Impact factor: 3.240