title: Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery.
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 combining125I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide.125I-UdR significantly decreased glioblastoma cell viability and migrationin vitroand the cell viability was further decreased by co-treatment with methotrexate and/or temozolomide. Intratumoral CED of methotrexate and125I-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 andpost-mortemhistology showed no signs of dose-limiting adverse effects. In conclusion, the multidrug approach consisting of CED of methotrexate and125I-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.
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Helge
authors.initials: H
authors.lastname: Thisgaard
authors.affiliation: Department of Clinical Research, University of Southern Denmark, Odense, Denmark;; Department of Pathology, Odense University Hospital, Odense, Denmark;; Department of Neurosurgery, Odense University Hospital, Odense, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Halle
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;; Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Aaberg-Jessen
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
authors.forename: Birgitte Brinkmann
authors.initials: BB
authors.lastname: Olsen
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
authors.forename: Anne Sofie Nautrup
authors.initials: AS
authors.lastname: Therkelsen
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
authors.forename: Johan Hygum
authors.initials: JH
authors.lastname: Dam
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Langkjær
authors.affiliation: Department of Clinical Research, University of Southern Denmark, Odense, Denmark;; Department of Pathology, Odense University Hospital, Odense, Denmark;; Department of Neurosurgery, Odense University Hospital, Odense, Denmark.
authors.forename: Sune
authors.initials: S
authors.lastname: Munthe
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
authors.forename: Kjell
authors.initials: K
authors.lastname: Någren
authors.affiliation: PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Poul Flemming
authors.initials: PF
authors.lastname: Høilund-Carlsen
authors.affiliation: Department of Clinical Research, University of Southern Denmark, Odense, Denmark;; Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Bjarne Winther
authors.initials: BW
authors.lastname: Kristensen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005909:Glioblastoma / Q000532:radiotherapy*; D064593:Heterografts; D007065:Idoxuridine / Q000008:administration & dosage*; D008727:Methotrexate / Q000008:administration & dosage; D011878:Radiotherapy / Q000379:methods*; D011923:Rats, Nude; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003606:Dacarbazine; D007065:Idoxuridine; D000077204:Temozolomide; D008727:Methotrexate
keywords: Auger-electron therapy; Glioblastoma; [125I]5-Iodo-2'-deoxyuridine; convection-enhanced delivery; temozolomide.