Development of cholecystokinin-B (CCK-B)/gastrin-receptor binding peptides: Preclinical evaluation of their diagnostic and therapeutic potential

Behr, Thomas M.; Béhé, Martin; Angerstein, C.; Gratz, S.; Hagemann, Lars; Jenner, Niels; Stiehler, Maik; Becker, Wolfgang

doi:10.1097/00006231-200006000-00088

Cited by 33 publications

(68 citation statements)

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“…Recently, its receptor CCK2R, which is shared with gastrin, has been described to be expressed at different intensities in normal and malignant C cells by Blakër et al [218]. No additional data has been published with regard to the putative functional role of CCK signalling in thyroid, however, there are initial encouraging therapeutic results with the use of CCK/Gastrin R2-binding peptides in patients with MTC [219,220].…”

Section: Other C-cell Secreted Peptidesmentioning

confidence: 99%

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells

Fernández-Santos¹,

García-Marín²,

Utrilla³

et al. 2012

Thyroid Hormone

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Section: Other C-cell Secreted Peptidesmentioning

confidence: 99%

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells

Fernández-Santos¹,

García-Marín²,

Utrilla³

et al. 2012

Thyroid Hormone

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“…Radiolabelled CCK analogues have been developed to target these receptors [10,59]. Behr et al used a different approach, applying minigastrin with high affinity for the CCK-B receptor and radiolabelled with 90 Y via stabilised DTPA (DTPA-D-Glu) as chelator for PRRT [9,12,14]. In eight patients with advanced metastatic disease who received escalating doses of 4×1,110-4×1,850 MBq/m 2 , a most promising 25% partial response rate was found.…”

Section: Current Status Of Use Of Radiolabelled Peptides For Tumour Tmentioning

confidence: 99%

“…Peptides have fast clearance, rapid tissue penetration and low antigenicity and can be produced easily. For evaluation of tumour receptor expression, different radiolabelled peptide analogues such as somatostatin, cholecystokinin (CCK), gastrin, bombesin, substance P, vasoactive intestinal peptide (VIP) and neuropeptide (NP)-Y analogues have been introduced [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. The most commonly used receptor-targeting agents are a variety of analogues of somatostatin.…”

Section: Introductionmentioning

confidence: 99%

Radiolabelled peptides for tumour therapy: current status and future directions

Jong

Kwekkeboom

Valkema

et al. 2003

Eur J Nucl Med Mol Imaging

108

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On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Changes in the density of these receptors during disease, e.g. overexpression in many tumours, provide the basis for new imaging methods. The first peptide analogues successfully applied for visualisation of receptor-positive tumours were radiolabelled somatostatin analogues. The next step was to label these analogues with therapeutic radionuclides for peptide receptor radionuclide therapy (PRRT). Results from preclinical and clinical multicentre studies have already shown an effective therapeutic response when using radiolabelled somatostatin analogues to treat receptor-positive tumours. Infusion of positively charged amino acids reduces kidney uptake, enlarging the therapeutic window. For PRRT of CCK-B receptor-positive tumours, such as medullary thyroid carcinoma, radiolabelled minigastrin analogues are currently being successfully applied. The combination of different therapy modalities holds interest as a means of improving the clinical therapeutic effects of radiolabelled peptides. The combination of different radionuclides, such as (177)Lu- and (90)Y-labelled somatostatin analogues, to reach a wider tumour region of high curability, has been described. A variety of other peptide-based radioligands, such as bombesin and NPY(Y(1)) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation. Multi-receptor tumour targeting using the combination of bombesin and NPY(Y(1)) analogues is promising for scintigraphy and PRRT of breast carcinomas and their lymph node metastases.

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“…The 111 In-labeled conjugates have been utilized as CCK-BR targeting radiopharmaceuticals in preclinical evaluation 10,11 and in patients with medullary thyroid carcinoma. 12 Behr and co-workers 13 have also utilized gastrin derivatives that are more selective for the CCK-BR compared to CCK analogs. They have tested a variety of CCK/gastrin-related peptides, all having in common the COOH-terminal CCK receptor binding tetrapeptide amide sequence Trp-Met-Asp-PheNH 2 .…”

Section: Cholecystokinin-b Receptors As Molecular Targetsmentioning

confidence: 99%

Radiolabeling approaches for cholecystokinin B receptor imaging

et al. 2002

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Regulatory peptides and their analogs are being extensively investigated as radiopharmaceuticals for cancer imaging. In particular, cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with (111)In or (99m)Tc for the purpose of developing radiopharmaceuticals for in vivo CCK-B receptor imaging. Labeling of CCK8 with (111)In was achieved at the N-terminus of the peptide by adding, in solid phase, a glutamate coupled diethylenetriaminepentaacetic acid (DTPA) moiety through a glycine linker, yielding DTPA-Glu-G-CCK8. For labeling with (99m)Tc, the CCK8 peptide was modified at its N-terminus by introducing, in the following order--cysteine, glycine, and a diphenylphosphinopropionyl moiety--giving a 10-residue peptide derivative, Phos-GC-CCK8. A cell culture model was developed for the purpose of evaluating the binding properties of these two ligands. The human epidermoid carcinoma cell line, A431, was transfected with a plasmid containing the full coding sequence of the human CCK-BR under a strong viral promoter, obtaining a number of receptors in the range of 2-5 x 10(6) per cell. Control cells were transfected with vector alone. An animal tumor model utilizing these two cell lines was developed to evaluate the specificity of interaction with the CCK-BR and biodistribution properties of the compounds. CCK-BR positive and control cells were subcutaneously injected in opposite flanks of CD1 female nude mice in order to obtain xenografts differing only in their ability to express CCK-B receptors. High performance liquid chromatography (HPLC) and other chromatographic methods were utilized to assess stability of the radiolabeled compounds after injection. Both (111)In-DTPA-Glu-G-CCK8 and (99m)Tc-Phos-GC-CCK8 showed similar binding affinities for cultured CCK-BR expressing cells, with dissociation constants in the range of 20-40 nM. With the two xenograft approach, we were able to demonstrate specific interaction with the receptor of both CCK analogs in our animal model. The data obtained shows rapid specific localization of both compounds on the CCK-BR overexpressing xenografts. Both tracers show rapid plasma clearance of unbound peptide. Clearance of (111)In-DTPA-Glu-G-CCK8 appears to be preferentially through the kidneys, whereas (99m)Tc-Phos-GC-CCK8 clearance occurs both through kidneys and the hepatobiliary system. Both our labeling approaches appear adequate for clinical use of peptide based radiopharmaceuticals, although (99m)Tc-Phos-GC-CCK8 shows elevated accumulation in the gastrointestinal tract, which causes high background activity.

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Development of cholecystokinin-B (CCK-B)/gastrin-receptor binding peptides: Preclinical evaluation of their diagnostic and therapeutic potential

Cited by 33 publications

References 0 publications

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells

Radiolabelled peptides for tumour therapy: current status and future directions

Radiolabeling approaches for cholecystokinin B receptor imaging

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