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Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate

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Abstract

Purpose

In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [177Lu-DOTA0,Tyr3]octreotate.

Methods

Male Lewis rats were injected with 278 or 555 MBq [177Lu-DOTA0,Tyr3]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of 99mTc-dimercaptosuccinic acid (DMSA), a measure of tubular function.

Results

Treatment with 555 MBq [177Lu-DOTA0,Tyr3]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [177Lu-DOTA0,Tyr3]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of 99mTc-DMSA SPECT scintigrams at 130 days after [177Lu-DOTA0,Tyr3]octreotate therapy correlated well with 1/creatinine (r 2=0.772, p<0.001).

Conclusion

Amifostine and lysine effectively decreased functional renal damage caused by high-dose [177Lu-DOTA0,Tyr3]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy.

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Acknowledgements

Flavio Forrer was supported by grants from the Swiss National Science Foundation and the Novartis Foundation Switzerland. The NanoSPECT was achieved through a grant of the Dutch organisation for scientific research (ZonMW). The authors wish to thank Ria van den Berg, Esther Slottje and Ron Briegoos for their expert help and effort.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Erasmus MC, ’s Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands

    Edgar J. Rolleman, Flavio Forrer, Bert Bernard, Magda Bijster, Roelf Valkema, Eric P. Krenning & Marion de Jong

  2. Department of Pathology, Erasmus MC, 3015 CE, Rotterdam, The Netherlands

    Marcel Vermeij

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  1. Edgar J. Rolleman
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  2. Flavio Forrer
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  3. Bert Bernard
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Correspondence to Edgar J. Rolleman.

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Rolleman, E.J., Forrer, F., Bernard, B. et al. Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate. Eur J Nucl Med Mol Imaging 34, 763–771 (2007). https://doi.org/10.1007/s00259-006-0291-3

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