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Pharmaceuticals 2017, 10(2), 57; doi:10.3390/ph10020057

A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice

1
Laboratory for Animal Model Pathology (LAMP), Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland
2
Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232 Villigen-PSI, Switzerland
3
Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK
4
Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Svend Borup Jensen and Klaus Kopka
Received: 5 May 2017 / Revised: 11 June 2017 / Accepted: 12 June 2017 / Published: 21 June 2017
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Abstract

Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage. View Full-Text
Keywords: radiation nephropathy; kidney; 177Lu; radiofolate; γ-H2AX; DNA double-strand breaks radiation nephropathy; kidney; 177Lu; radiofolate; γ-H2AX; DNA double-strand breaks
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Pellegrini, G.; Siwowska, K.; Haller, S.; Antoine, D.J.; Schibli, R.; Kipar, A.; Müller, C. A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice. Pharmaceuticals 2017, 10, 57.

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