Long-term toxicity of [(177)Lu-DOTA (0),Tyr (3)]octreotate in rats.
OBJECTIVE
Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models.


RESULTS
Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2x278 MBq groups. Three doses of 185 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469+/-18, 134+/-70 and 65+/-15 micromol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria.


CONCLUSIONS
Injection of high doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.
Rolleman
Edgar J
EJ
Department of Nuclear Medicine, Erasmus MC Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands. e.rolleman@erasmusmc.nl
Krenning
Eric P
EP
Bernard
Bert F
BF
de Visser
Monique
M
Bijster
Magda
M
Visser
Theo J
TJ
Vermeij
Marcel
M
Lindemans
Jan
J
de Jong
Marion
M
D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects*; D001855:Bone Marrow Diseases / Q000175:diagnosis / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000528:radiation effects*; D007674:Kidney Diseases / Q000175:diagnosis / Q000209:etiology*; D007928:Lethal Dose 50; D008137:Longitudinal Studies; D008297:Male; D015282:Octreotide / Q000031:analogs & derivatives* / Q000633:toxicity; D009942:Organometallic Compounds / Q000633:toxicity*; D011832:Radiation Injuries / Q000175:diagnosis / Q000209:etiology*; D019275:Radiopharmaceuticals / Q000633:toxicity; D051381:Rats; D011917:Rats, Inbred Lew
D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C447941:lutetium Lu 177 dotatate; D015282:Octreotide