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Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute

Journal article
Authors C. Muller
M. D. Leal
M. D. Dominietto
C. A. Umbricht
S. Safai
R. L. Perrin
M. Egloff
Peter Bernhardt
N. P. van der Meulen
D. C. Weber
R. Schibli
A. J. Lomax
Published in Pharmaceutics
Volume 11
Issue 9
Publication year 2019
Published at Institute of Clinical Sciences, Department of Radiation Physics
Language en
Links dx.doi.org/10.3390/pharmaceutics110...
Keywords proton therapy, targeted radionuclide therapy, PET imaging, folate receptor, PSMA, Lu-177, long-term outcomes, beam therapy, tumor-therapy, radiotherapy, cancer, radioimmunotherapy
Subject categories Cancer and Oncology, Radiology

Abstract

Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using Lu-177-folate and Lu-177-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by beta over bar -particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy.

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