Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate.
OBJECTIVE
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 [(177)Lu-DOTA(0),Tyr(3)]octreotate.


METHODS
Male Lewis rats were injected with 278 or 555 MBq [(177)Lu-DOTA(0),Tyr(3)]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 (99m)Tc-dimercaptosuccinic acid (DMSA), a measure of tubular function.


RESULTS
Treatment with 555 MBq [(177)Lu-DOTA(0),Tyr(3)]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 [(177)Lu-DOTA(0),Tyr(3)]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 (99m)Tc-DMSA SPECT scintigrams at 130 days after [(177)Lu-DOTA(0),Tyr(3)]octreotate therapy correlated well with 1/creatinine (r(2)=0.772, p<0.001).


CONCLUSIONS
Amifostine and lysine effectively decreased functional renal damage caused by high-dose [(177)Lu-DOTA(0),Tyr(3)]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy.
Rolleman
Edgar J
EJ
Department of Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. e.rolleman@erasmusmc.nl.
Forrer
Flavio
F
Department of Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
Bernard
Bert
B
Department of Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
Bijster
Magda
M
Department of Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
Vermeij
Marcel
M
Department of Pathology, Erasmus MC, 3015 CE, Rotterdam, The Netherlands.
Valkema
Roelf
R
Department of Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
Krenning
Eric P
EP
Department of Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
de Jong
Marion
M
Department of Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
D004999:Amifostine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D003404:Creatinine / Q000378:metabolism; D007668:Kidney / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D009369:Neoplasms / Q000532:radiotherapy*; D015282:Octreotide / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D009942:Organometallic Compounds / Q000627:therapeutic use* / Q000633:toxicity*; D011507:Proteinuria / Q000378:metabolism; D011832:Radiation Injuries / Q000175:diagnosis / Q000517:prevention & control*; D019275:Radiopharmaceuticals / Q000627:therapeutic use* / Q000633:toxicity*; D051381:Rats; D011917:Rats, Inbred Lew; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C447941:lutetium Lu 177 dotatate; D003404:Creatinine; D008239:Lysine; D004999:Amifostine; D015282:Octreotide