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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2016
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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. |
format | Online Article Text |
id | pubmed-5135448 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
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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