lutetium-lu-177-dotatate and Body-Weight

In peptide receptor radionuclide therapy for neuroendocrine tumors the main dose-limiting tissue is found in the kidneys because of tubular reabsorption and retention of radioactivity. The aim of this study was to quantify late effects in renal cortex of nude mice exposed to high amounts of [(177)Lu]-DOTA-Tyr(3)-octreotate ([(177)Lu]-DOTATATE), and to determine whether a threshold dose value exists for these findings.. Nude mice were exposed to 90, 120 or 150 MBq of [(177)Lu]-DOTATATE. Renal toxicity was evaluated up to 6 months after injection. Blood samples were collected to examine renal functional markers, and after sacrifice at 6 months changes in renal morphology were explored. Tissue damage was estimated by quantifying the relative area of the different subunits in the renal cortex using point counting. Additional morphological signs of radiation damage were also noted. The absorbed doses to the kidneys were estimated by previously determined kidney pharmacokinetics and Monte Carlo simulations for different assumptions regarding the activity distribution.. Increased serum creatinine and urea values indicated long-term renal toxicity. The tissue area occupied by proximal tubules decreased with increasing doses of [(177)Lu]-DOTATATE, whereas the other subunits in cortex slightly increased. The mean absorbed dose in the renal cortex for [(177)Lu]-DOTATATE was estimated to be 35-58 Gy for the different groups of animals. A dose-response relationship was observed for proximal tubular damage, and a threshold dose value of 24 Gy (BED 37 Gy) was determined.. Selective morphological changes in kidney cortex of nude mice were quantified and appeared in a dose dependent manner after injection of high amounts of [(177)Lu]-DOTATATE.

Topics: Animals; Biomarkers; Body Weight; Bone Marrow; Female; Injections; Kidney; Kidney Cortex; Kidney Tubules, Proximal; Mice; Mice, Nude; Octreotide; Organometallic Compounds; Radiation Dosage; Radiometry; Toxicity Tests

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.. 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.. 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).. 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.

Topics: Amifostine; Animals; Body Weight; Creatinine; Kidney; Lysine; Male; Neoplasms; Octreotide; Organometallic Compounds; Proteinuria; Radiation Injuries; Radiopharmaceuticals; Rats; Rats, Inbred Lew; Tomography, Emission-Computed, Single-Photon