Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA(0),Tyr(3)]octreotate.

Purpose: Adequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys, the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of the radiopharmaceutical in the blood.

Renal uptake and retention of radiolabeled somatostatin, bombesin, neurotensin, minigastrin and CCK analogues: species and gender differences.

Introduction: During therapy with radiolabeled peptides, the kidney is most often the critical organ. Newly developed peptides are evaluated preclinically in different animal models before their application in humans. In this study, the renal retention of several radiolabeled peptides was compared in male and female rats and mice.

Five Stabilized 111In-labeled neurotensin analogs in nude mice bearing HT29 tumors.

Neurotensin (NT) receptors are overexpressed in different human tumors, such as human ductal pancreatic adenocarcinoma. New stable neurotensin analogs with high receptor affinity have been synthesized by replacing arginine residues with lysine and arginine derivatives. The aim of this study was to explore the biodistribution, tumor uptake, kidney localization, and stability characteristics of these new analogs in order to develop new diagnostic tools for exocrine pancreatic cancer.

Diagnostic versus therapeutic doses of [(177)Lu-DOTA-Tyr(3)]-octreotate: uptake and dosimetry in somatostatin receptor-positive tumors and normal organs.

Aim: The aim of this study was to investigate the influence of a diagnostic versus therapeutic dose of [(177)Lu-DOTA-Tyr(3)]octreotate on the uptake, effects, and dosimetry in somatostatin receptor subtype 2(sst2)-positive tumors and normal organs in a rat tumor model.

Materials And Methods: Lewis rats bearing rat pancreatic CA20948-tumor grafts were injected intravenously with different amounts of radioactivity and peptide of [(177)Lu-DOTA-Tyr(3)]octreotate: 3 MBq/0.5 microg (group A), 3 MBq/15 microg (group B), 300 MBq/15 microg (group C), and 555 MBq/15 microg (group D).

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

Purpose And Methods: 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.

[(99m)Tc]Demotate 2 in the detection of sst(2)-positive tumours: a preclinical comparison with [(111)In]DOTA-tate.

Purpose: The aim of this study was to evaluate [(99m)Tc]Demotate 2 ([(99m)Tc-N(4) (0-1),Asp(0),Tyr(3)]octreotate) as a candidate for in vivo imaging of sst(2)-positive tumours and to compare it with [(111)In]DOTA-tate ([(111)In-DOTA(0),Tyr(3)]octreotate).

Methods: Labelling of Demotate 2 with (99m)Tc was performed at room temperature using SnCl(2) as reductant in the presence of citrate at alkaline pH. Radiochemical analysis involved ITLC and HPLC methods.

Anticancer activity of targeted proapoptotic peptides.

Unlabelled: Tumor-induced angiogenesis can be targeted by RGD (Arg-Gly-Asp) peptides, which bind to alpha(v)beta(3)-receptors upregulated on angiogenic endothelial cells. RGD-containing peptides are capable of inducing apoptosis through direct activation of procaspase-3 to caspase-3 in cells. Additionally, tumor cells overexpressing somatostatin receptors can be targeted by somatostatin analogs.

Localisation and mechanism of renal retention of radiolabelled somatostatin analogues.

Purpose: Radiolabelled somatostatin analogues, such as octreotide and octreotate, are used for tumour scintigraphy and radionuclide therapy. The kidney is the most important critical organ during such therapy owing to the reabsorption and retention of radiolabelled peptides. The aim of this study was to investigate in a rat model both the localisation and the mechanism of renal uptake after intravenous injection of radiolabelled somatostatin analogues.

Radiolabelling DOTA-peptides with 68Ga.

Purpose: A new field of interest is the application of 68Ga-labelled DOTA-conjugated peptides for positron emission tomography (PET). The commercially available or house-made generators require time-consuming and tedious handling of the eluate. Radiolabelling at high specific activities without further purification is not possible, while high specific activities are necessary for peptides that potentially display pharmacological side-effects.

Combination radionuclide therapy using 177Lu- and 90Y-labeled somatostatin analogs.

Unlabelled: Peptide receptor-targeted radionuclide therapy of somatostatin receptor-expressing tumors is a promising application of radiolabeled somatostatin analogs. Suitable radionuclides are (90)Y, a pure, high-energy beta-emitter (2.27 MeV), and (177)Lu, a medium-energy beta-emitter (0.

Increased cell death after therapy with an Arg-Gly-Asp-linked somatostatin analog.

Unlabelled: Receptor-targeted scintigraphy and radionuclide therapy with radiolabeled somatostatin analogs are successfully applied for somatostatin receptor-positive tumors. The synergistic effects of an apoptosis-inducing factor, for example, the Arg-Gly-Asp (RGD) motif, can increase the radiotherapeutic efficacy of these peptides. Hence, the tumoricidal effects of the hybrid peptide RGD-diethylaminetriaminepentaacetic acid (DTPA)-Tyr3-octreotate (cyclic[c](Arg-Gly-Asp-D-Tyr-Asp)-Lys(DTPA)-D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr), hereafter referred to as RGD-DTPA-octreotate, were evaluated in comparison with those of RGD (c(Arg-Gly-Asp-D-Tyr-Asp)) and Tyr3-octreotate (D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr).

Norharman and alcohol-dependency in male Wistar rats.

We examined the effects of ethanol ingestion to rats on levels of the beta-carboline norharman in plasma, brain and liver at the end of ethanol ingestion and 10 h after withdrawal. We also investigated the effect of exogenously administered norharman on the behavioural signs of alcohol withdrawal. Ethanol was given by a liquid diet for 21 days.

Reduction of skeletal accumulation of radioactivity by co-injection of DTPA in [90Y-DOTA0,Tyr3]octreotide solutions containing free 90Y3+.

Peptide receptor-targeted radionuclide therapy is nowadays being performed with radiolabeled DOTA-conjugated peptides, such as [90Y-DOTA0,Tyr3]octreotide (also known as OctreoTher or 90Y-DOTATOC). The incorporation of 90Y3+ is typically > or = 99%, however, since a total patient dose can be as high as 26 GBq or 700 mCi the amount of free 90Y3+ (= non-DOTA-incorporated) can be substantial. Free 90Y3+ accumulates in bone with undesired radiation of bone marrow as a consequence.

Uptake of [111In-DTPA0]octreotide in the rat kidney is inhibited by colchicine and not by fructose.

Unlabelled: The high renal uptake of radiolabeled somatostatin analogs is dose limiting. Lowering this uptake permits higher radioactivity doses and, thus, tumor doses to be administered. We tested the effects of the microtubule drug colchicine on renal uptake of [(111)In-DTPA(0)]octreotide.

Tyr3-octreotide and Tyr3-octreotate radiolabeled with 177Lu or 90Y: peptide receptor radionuclide therapy results in vitro.

Somatostatin analogs promising for peptide receptor scintigraphy (PRS) and peptide receptor radionuclide therapy (PRRT) are D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol) (Tyr 3-octreotide) and D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr (tyr3-octreotate). For radiotherapeutic applications these peptides are being labeled with the beta(-) particle emitters 177Lu or 90Y. We evaluated the therapeutic effects of these analogs chelated with tetra-azacyclododecatatro-acetic acid (DOTA) and labeled with 90Y or 177Lu in an in vitro colony-forming assay using the rat pancreatic tumor cell line CA20948.

DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals.

Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours.

Anti-tumor effect and increased survival after treatment with [177Lu-DOTA0,Tyr3]octreotate in a rat liver micrometastases model.

Peptide receptor scintigraphy with [(111)In-DTPA(0)]octreotide (a stabilized radiolabeled somatostatin (SS) analogue, OctreoScan) is widely used for the visualization and staging of somatostatin receptor-positive tumors. The application of likewise somatostatin analogues as vehicle for the deliverance of radionuclides to somatostatin receptor-positive targets are now in use for peptide receptor-targeted radionuclide therapy (PRRT). Currently preclinical and clinical investigation are ongoing trying to find the optimal combination of radionuclide and ligand.

The addition of DTPA to [177Lu-DOTA0,Tyr3]octreotate prior to administration reduces rat skeleton uptake of radioactivity.

Peptide receptor-targeted radionuclide therapy is nowadays also being performed with DOTA-conjugated peptides, such as [DOTA(0),Tyr(3)]octreotate, labelled with radionuclides like (177)Lu. The incorporation of (177)Lu is typically >/=99.5%; however, since a total patient dose can be as high as 800 mCi, the amount of free (177)Lu(3+) (= non-DOTA-incorporated) can be substantial.

Peptide receptor radionuclide therapy in vitro using [111In-DTPA0]octreotide.

Unlabelled: Peptide receptor radionuclide therapy (PRRT) using [(111)In-DTPA(0)]octreotide (where DTPA is diethylenetriaminepentaacetic acid) is feasible because, besides gamma-radiation, (111)In emits both therapeutic Auger and internal conversion electrons having a tissue penetration of 0.02-10 and 200-500 micro m, respectively. The aim of this study was to investigate the therapeutic effects of [(111)In-DTPA(0)]octreotide in a single-cell model including the effects of incubation time, radiation dose, and specific activity of [(111)In-DTPA(0)]octreotide.

Preclinical comparison of (111)In-labeled DTPA- or DOTA-bombesin analogs for receptor-targeted scintigraphy and radionuclide therapy.

Unlabelled: The 14-amino-acid peptide bombesin (BN) has a high affinity for the gastrin-releasing peptide (GRP) receptor that is expressed by a variety of tumors. Recently, high densities of GRP receptors were identified by in vitro receptor autoradiography in human prostate and breast carcinomas using [(125)I-Tyr(4)]BN as radioligand. Radiometal-labeled diethylenetriaminepentaacetic acid (DTPA)-BN derivatives are potentially useful radioligands for receptor-targeted scintigraphy and radiotherapy of GRP receptor-expressing tumors.