Auger electron therapy of glioblastoma using [125I]5-iodo-2'-deoxyuridine and concomitant chemotherapy - Evaluation of a potential treatment strategy.

INTRODUCTION: Treatment of glioblastomas (GBM) using the Auger electron emitting compound [125I]5-Iodo-2'-deoxyuridine ([125I]I-UdR), combined with the thymidylate synthase inhibitor methotrexate (MTX) and concomitant chemotherapy with temozolomide (TMZ) has recently shown very promising therapeutic effects in vitro and in vivo in animals. The aim of the current study was to investigate if the therapeutic effects of this multimodal treatment strategy could be further increased by the thymidylate synthase inhibitor, 5-fluoro-2'-deoxyuridine (F-UdR), in comparison to MTX, and if the co-treatment should be given in a neoadjuvant or adjuvant setting. METHODS: A patient-derived GBM cancer stem cell (CSC)-enriched cell line, grown as neurospheres, was employed to evaluate DNA-incorporation of [125I]I-UdR, determined by a DNA precipitation assay, using either pre-treatment or co-treatment with MTX or F-UdR. The therapeutic effects in the CSC-enriched cell line after exposure to various combinations of MTX, F-UdR, TMZ and [125I]I-UdR were also investigated by a CellTiter-Blue assay. RESULTS: The highest general increase in [125I]I-UdR incorporation was observed with F-UdR co-treatment, which resulted in approx. 2.5-fold increase in the DNA-associated activity. Also the cell viability was significantly decreased when F-UdR was combined with [125I]I-UdR compared to [125I]I-UdR alone at all activity concentrations tested. MTX was redundant when combined with 400 and 500 Bq/ml [125I]I-UdR. TMZ was effective in combination with either [125I]I-UdR alone or with both thymidylate synthase inhibitors combined with 50-100 Bq/ml [125I]I-UdR. CONCLUSIONS: Overall, our study revealed a higher incorporation and therapeutic effect of [125I]I-UdR when GBM cells were co-treated with F-UdR compared to MTX. The therapeutic effects were further increased when TMZ was combined with [125I]I-UdR in combination with the thymidylate synthase inhibitors. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Auger electron therapy in combination with thymidylate synthase inhibition and concomitant chemotherapy has the potential to become a future therapeutic treatment option for patients with glioblastoma.

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 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.