Article

Long-term toxicity of [(177)Lu-DOTA (0),Tyr (3)]octreotate in rats.

Department of Nuclear Medicine, Erasmus MC Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
European journal of nuclear medicine and molecular imaging (impact factor: 4.99). 02/2007; 34(2):219-27. DOI:10.1007/s00259-006-0232-1
Source: PubMed

ABSTRACT 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.
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.
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.

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    M Fani, H R Maecke, S M Okarvi
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    ABSTRACT: Human cancer cells overexpress many peptide receptors as molecular targets. Radiolabeled peptides that bind with high affinity and specificity to the receptors on tumor cells hold great potential for both diagnostic imaging and targeted radionuclide therapy. The advantage of solid-phase peptide synthesis, the availability of different chelating agents and prosthetic groups and bioconjugation techniques permit the facile preparation of a wide variety of peptide-based targeting molecules with diverse biological and tumor targeting properties. Some of these peptides, including somatostatin, bombesin, vasoactive intestinal peptide, gastrin, neurotensin, exendin and RGD are currently under investigation. It is anticipated that in the near future many of these peptides may find applications in nuclear oncology. This article presents recent developments in the field of small peptides, and their applications in the diagnosis and treatment of cancer.
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Keywords

different doses
 
dose fractionation
 
flat epithelium
 
functional damage
 
histological damage
 
long-term renal toxicity
 
Lysine co-administration
 
lysine co-injection
 
p<0.001). Renal histological damage scores
 
peptide receptor radionuclide therapy
 
promising results
 
proximal tubules
 
radiolabelled somatostatin analogues
 
Renal damage scores
 
serum creatinine
 
severe renal damage
 
Significant renal toxicity
 
tumour control
 
weekly doses
 
weekly treatments