Dose-response effect of Gelofusine on renal uptake and retention of radiolabelled octreotate in rats with CA20948 tumours.
OBJECTIVE
Peptide receptor radionuclide therapy using β-emitting radiolabelled somatostatin analogues like DOTA,Tyr3-octreotate shows beneficial results in patients suffering from somatostatin receptor overexpressing tumours. However, after high-dose therapy partial renal reabsorption of radiopeptides may lead to nephrotoxicity. Co-infusion of lysine/arginine lowers renal retention of these radiopeptides without affecting tumour uptake. Recently co-administration of Gelofusine has been described to have a comparable kidney-protecting effect in rats. In the present study optimal dosing of Gelofusine co-administration was studied in tumour-bearing rats.


METHODS
Doses of 40, 80, 120 or 160 mg/kg Gelofusine were co-injected with 15 µg DOTA,Tyr3-octreotate, labelled with 3 MBq 111In for biodistribution (24 h post-injection, n = 4 per group) and with 60 MBq 111In for microSPECT imaging experiments at 3, 24 and 48 h post-injection. An additional group of rats received 80 mg/kg Gelofusine plus 400 mg/kg lysine co-injection. Biodistribution studies were performed both in older (475 g) and younger (300 g) rats, the latter bearing CA20948 tumours.


RESULTS
Co-injection of 40 mg/kg Gelofusine resulted in 40-50% reduction of renal uptake and retention of 111In-DOTA,Tyr3-octreotate, whereas higher doses further increased the reduction to 50-60% in both groups of rats. Combining Gelofusine and lysine caused 70% reduction of renal uptake. The uptake of radiolabelled octreotate both in somatostatin receptor-expressing normal tissues and tumours was not affected by Gelofusine co-injection.


CONCLUSIONS
In rats co-injection of 80 mg/kg Gelofusine resulted in maximum reduction of renal retention of 111In-DOTA,Tyr3-octreotate, which was further improved when combined with lysine. Tumour uptake of radiolabelled octreotate was not affected, resulting in an increased tumour to kidney ratio.
Melis
Marleen
M
Department of Nuclear Medicine, Erasmus MC Rotterdam, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. m.melis@erasmusmc.nl
Bijster
Magda
M
de Visser
Monique
M
Konijnenberg
Mark W
MW
de Swart
Jan
J
Rolleman
Edgar J
EJ
Boerman
Otto C
OC
Krenning
Eric P
EP
de Jong
Marion
M
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D007553:Isotope Labeling; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D010456:Peptides, Cyclic / Q000378:metabolism* / Q000493:pharmacokinetics; D011097:Polygeline / Q000494:pharmacology*; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C470036:octreotate, Tyr(3)-; D011097:Polygeline