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

Helge Thisgaard, Bo Halle, Charlotte Aaberg-Jessen, Birgitte Brinkmann Olsen, Anne Sofie Nautrup Therkelsen, Johan Hygum Dam, Niels Langkjær, Sune Munthe, Kjell Någren, Poul Flemming Høilund-Carlsen, Bjarne Winther Kristensen

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Abstract

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 [ 125I]5-Iodo-2'-deoxyuridine ( 125I-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 125I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide. 125I-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 125I-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 125I-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.

Original languageEnglish
JournalTheranostics
Volume6
Issue number12
Pages (from-to)2278-2291
ISSN1838-7640
DOIs
Publication statusPublished - 1. Jan 2016

Keywords

  • Auger-electron therapy
  • Convection-enhanced delivery
  • Glioblastoma
  • Temozolomide
  • [ I]5-Iodo-2'-deoxyuridine
  • Antineoplastic Agents/administration & dosage
  • Glioblastoma/radiotherapy
  • Treatment Outcome
  • Rats, Nude
  • Methotrexate/administration & dosage
  • Animals
  • Heterografts
  • Survival Analysis
  • Dacarbazine/administration & dosage
  • Drug Therapy, Combination
  • Idoxuridine/administration & dosage
  • Radiotherapy/methods
  • Disease Models, Animal

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