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Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery

Glioblastoma, the most common and malignant primary brain tumor, always recurs after standard treatment. Therefore, promising new therapeutic approaches are needed. Short-range Auger-electron-emitters carry the ability of causing highly damaging radiation effects in cells. The aim of this study was...

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Autores principales: Thisgaard, Helge, Halle, Bo, Aaberg-Jessen, Charlotte, Olsen, Birgitte Brinkmann, Therkelsen, Anne Sofie Nautrup, Dam, Johan Hygum, Langkjær, Niels, Munthe, Sune, Någren, Kjell, Høilund-Carlsen, Poul Flemming, Kristensen, Bjarne Winther
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135448/
https://www.ncbi.nlm.nih.gov/pubmed/27924163
http://dx.doi.org/10.7150/thno.15898
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author Thisgaard, Helge
Halle, Bo
Aaberg-Jessen, Charlotte
Olsen, Birgitte Brinkmann
Therkelsen, Anne Sofie Nautrup
Dam, Johan Hygum
Langkjær, Niels
Munthe, Sune
Någren, Kjell
Høilund-Carlsen, Poul Flemming
Kristensen, Bjarne Winther
author_facet Thisgaard, Helge
Halle, Bo
Aaberg-Jessen, Charlotte
Olsen, Birgitte Brinkmann
Therkelsen, Anne Sofie Nautrup
Dam, Johan Hygum
Langkjær, Niels
Munthe, Sune
Någren, Kjell
Høilund-Carlsen, Poul Flemming
Kristensen, Bjarne Winther
author_sort Thisgaard, Helge
collection PubMed
description Glioblastoma, the most common and malignant primary brain tumor, always recurs after standard treatment. Therefore, promising new therapeutic approaches are needed. Short-range Auger-electron-emitters carry the ability of causing highly damaging radiation effects in cells. The aim of this study was to test the effect of [(125)I]5-Iodo-2'-deoxyuridine ((125)I-UdR, a radioactive Auger-electron-emitting thymidine analogue) Auger-therapy on immature glioblastoma spheroid cultures and orthotopic xenografted glioblastoma-bearing rats, the latter by means of convection-enhanced delivery (CED). Moreover, we aimed to determine if the therapeutic effect could be enhanced when combining (125)I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide. (125)I-UdR significantly decreased glioblastoma cell viability and migration in vitro and the cell viability was further decreased by co-treatment with methotrexate and/or temozolomide. Intratumoral CED of methotrexate and (125)I-UdR with and without concomitant systemic temozolomide chemotherapy significantly reduced the tumor burden in orthotopically xenografted glioblastoma-bearing nude rats. Thus, 100% (8/8) of the animals survived the entire observation period of 180 days when subjected to the combined Auger-chemotherapy while 57% (4/7) survived after the Auger-therapy alone. No animals (0/8) treated with temozolomide alone survived longer than 50 days. Blood samples and post-mortem histology showed no signs of dose-limiting adverse effects. In conclusion, the multidrug approach consisting of CED of methotrexate and (125)I-UdR with concomitant systemic temozolomide was safe and very effective leading to 100% survival in an orthotopic xenograft glioblastoma model. Therefore, this therapeutic strategy may be a promising option for future glioblastoma therapy.
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spelling pubmed-51354482016-12-06 Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery Thisgaard, Helge Halle, Bo Aaberg-Jessen, Charlotte Olsen, Birgitte Brinkmann Therkelsen, Anne Sofie Nautrup Dam, Johan Hygum Langkjær, Niels Munthe, Sune Någren, Kjell Høilund-Carlsen, Poul Flemming Kristensen, Bjarne Winther Theranostics Research Paper Glioblastoma, the most common and malignant primary brain tumor, always recurs after standard treatment. Therefore, promising new therapeutic approaches are needed. Short-range Auger-electron-emitters carry the ability of causing highly damaging radiation effects in cells. The aim of this study was to test the effect of [(125)I]5-Iodo-2'-deoxyuridine ((125)I-UdR, a radioactive Auger-electron-emitting thymidine analogue) Auger-therapy on immature glioblastoma spheroid cultures and orthotopic xenografted glioblastoma-bearing rats, the latter by means of convection-enhanced delivery (CED). Moreover, we aimed to determine if the therapeutic effect could be enhanced when combining (125)I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide. (125)I-UdR significantly decreased glioblastoma cell viability and migration in vitro and the cell viability was further decreased by co-treatment with methotrexate and/or temozolomide. Intratumoral CED of methotrexate and (125)I-UdR with and without concomitant systemic temozolomide chemotherapy significantly reduced the tumor burden in orthotopically xenografted glioblastoma-bearing nude rats. Thus, 100% (8/8) of the animals survived the entire observation period of 180 days when subjected to the combined Auger-chemotherapy while 57% (4/7) survived after the Auger-therapy alone. No animals (0/8) treated with temozolomide alone survived longer than 50 days. Blood samples and post-mortem histology showed no signs of dose-limiting adverse effects. In conclusion, the multidrug approach consisting of CED of methotrexate and (125)I-UdR with concomitant systemic temozolomide was safe and very effective leading to 100% survival in an orthotopic xenograft glioblastoma model. Therefore, this therapeutic strategy may be a promising option for future glioblastoma therapy. Ivyspring International Publisher 2016-09-29 /pmc/articles/PMC5135448/ /pubmed/27924163 http://dx.doi.org/10.7150/thno.15898 Text en © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.
spellingShingle Research Paper
Thisgaard, Helge
Halle, Bo
Aaberg-Jessen, Charlotte
Olsen, Birgitte Brinkmann
Therkelsen, Anne Sofie Nautrup
Dam, Johan Hygum
Langkjær, Niels
Munthe, Sune
Någren, Kjell
Høilund-Carlsen, Poul Flemming
Kristensen, Bjarne Winther
Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery
title Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery
title_full Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery
title_fullStr Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery
title_full_unstemmed Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery
title_short Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery
title_sort highly effective auger-electron therapy in an orthotopic glioblastoma xenograft model using convection-enhanced delivery
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135448/
https://www.ncbi.nlm.nih.gov/pubmed/27924163
http://dx.doi.org/10.7150/thno.15898
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