ET-22 * CONVECTION-ENHANCED DELIVERY OF THE AUGER-ELECTRON-EMITTER 125I-UdR: A HIGHLY EFFICIENT THERAPY IN AN ORTHOTOPIC GLIOBLASTOMA XENOGRAFT MODEL

Abstract

BACKGROUND: Glioblastomas (GBMs), the most common and malignant primary brain tumors, always recur after standard treatment. In order to develop more efficient therapies, we tested a novel therapeutic approach using the radioactive Auger-electron-emitter (AEE) [125I]5-Iodo-2'-deoxyuridine (125I-UdR). This drug incorporates into DNA of dividing cells and upon decay emission of Auger-electrons causes clusters of double strand breaks leading to cell death. METHODS: In vitro, cells from two GBM spheroid cultures (T78 & T87) were exposed to either 125I-UdR or 127I-UdR (non-radioactive analogue) and tumor cell viability and migration were measured. In vivo, nude rats were implanted orthotopically with T87 cells and after tumor formation micro infusion pumps were implanted enabling direct intratumoral convection-enhanced delivery (CED). Animals were divided into three groups (I-III). Group I (n = 8) was treated with 127I-UdR by CED, group II (n = 7) with neoadjuvant methotrexate (MTX) + 125I-UdR by CED and group III with neoadjuvant MTX + 125I-UdR by CED and concomitant systemic temozolomide (TMZ). Rats were followed for 180 days post-treatment with repeated [11C]methylaminoisobutyric acid ([11C]MeAIB) positron emission tomography scans and blood sampling. Single photon emission computed tomography/computed tomography (SPECT/CT) scans were performed to evaluate 125I-UdR distribution. Additionally, post-mortem histological examination of brain, liver, kidneys and thyroid gland was performed. RESULTS: In vitro, 125I-UdR significantly decreased GBM cell viability and migration. In group I, no animals (8/8) survived longer than 23 days after treatment start. In group II, 4/7 animals survived the entire observation period of 180 days. In group III, all animals (8/8) survived the entire observation period. SPECT/CT showed a widespread intracerebral distribution of 125I-UdR, while blood samples and post-mortem histology revealed no signs of dose-limiting adverse effects. CONCLUSIONS: The novel therapeutic approach with CED of MTX and the AEE-compound 125I-UdR in combination with systemic TMZ seemed safe and very efficient in the orthotopic GBM model.