scholarly journals Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [177Lu]Lu-OPS201 Compared to the Agonist [177Lu]Lu-DOTA-TATE

2021 ◽  
Vol 14 (12) ◽  
pp. 1265
Author(s):  
Rosalba Mansi ◽  
Pascale Plas ◽  
Georges Vauquelin ◽  
Melpomeni Fani
Keyword(s):  
Binding Sites ◽  
Therapeutic Efficacy ◽  
Somatostatin Receptor ◽  
In Vitro Study ◽  
Receptor Subtype ◽  
High Concentration ◽  
Cellular Mechanisms ◽  
Competition Binding ◽  
Somatostatin Receptor Subtype 2

Treatment of neuroendocrine tumours with the radiolabelled somatostatin receptor subtype 2 (SST2) peptide agonist [177Lu]Lu-DOTA-TATE is effective and well-established. Recent studies suggest improved therapeutic efficacy using the SST2 peptide antagonist [177Lu]Lu-OPS201. However, little is known about the cellular mechanisms that lead to the observed differences. In the present in vitro study, we compared kinetic binding, saturation binding, competition binding, cellular uptake and release of [177Lu]Lu-OPS201 versus [177Lu]Lu-DOTA-TATE using HEK cells stably transfected with the human SST2. While [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE exhibited comparable affinity (KD, 0.15 ± 0.003 and 0.08 ± 0.02 nM, respectively), [177Lu]Lu-OPS201 recognized four times more binding sites than [177Lu]Lu-DOTA-TATE. Competition assays demonstrated that a high concentration of the agonist displaced only 30% of [177Lu]Lu-OPS201 bound to HEK-SST2 cell membranes; an indication that the antagonist binds to additional sites that are not recognized by the agonist. [177Lu]Lu-OPS201 showed faster association and slower dissociation than [177Lu]Lu-DOTA-TATE. Whereas most of [177Lu]Lu-OPS201 remained at the cell surface, [177Lu]Lu-DOTA-TATE was almost completely internalised inside the cell. The present data identified distinct differences between [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE regarding the recognition of receptor binding sites (higher for [177Lu]Lu-OPS201) and their kinetics (faster association and slower dissociation of [177Lu]Lu-OPS201) that explain, to a great extent, the improved therapeutic efficacy of [177Lu]Lu-OPS201 compared to [177Lu]Lu-DOTA-TATE.

Somatostatin Receptor Subtype 2 Gene Therapy Inhibits Pancreatic Cancer in Vitro

2002 ◽  
Vol 105 (1) ◽  
pp. 58-64 ◽  
Author(s):  
William E. Fisher ◽  
YuanQing Wu ◽  
Felipe Amaya ◽  
David H. Berger
Keyword(s):  
Pancreatic Cancer ◽  
Gene Therapy ◽  
Somatostatin Receptor ◽  
Receptor Subtype ◽  
Somatostatin Receptor Subtype 2

scholarly journals Internalized Somatostatin Receptor Subtype 2 in Neuroendocrine Tumors of Octreotide-Treated Patients

2010 ◽  
Vol 95 (5) ◽  
pp. 2343-2350 ◽  
Author(s):  
Jean Claude Reubi ◽  
Beatrice Waser ◽  
Renzo Cescato ◽  
Beat Gloor ◽  
Christoph Stettler ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Somatostatin Receptor ◽  
Receptor Autoradiography ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
High Dose ◽  
Somatostatin Receptor Subtype 2 ◽  
In Vitro Receptor Autoradiography

Abstract Context: Somatostatin receptor subtype 2 (sst2) is widely expressed in neuroendocrine tumors and can be visualized immunohistochemically at the cell membrane for diagnostic purposes. Recently, it has been demonstrated in animal sst2 tumor models in vivo that somatostatin analog treatment was able to induce a complete internalization of the tumor sst2. Patients and Methods: In the present study, we evaluated whether sst2 expressed in neuroendocrine tumors of patients treated with octreotide are also internalized. Tumor samples were assessed in patients that were treated with various octreotide modalities before and during surgery and compared with tumor samples from untreated patients. Sst2 immunohistochemistry was performed in all samples with three different sst2 antibodies (R2-88, UMB-1, and SS-800). Sst2 receptor expression was confirmed by immunoblotting and in vitro receptor autoradiography. Results: Patients receiving a high dose of octreotide showed predominantly internalized sst2, and patients with a low dose of octreotide had a variable ratio of internalized vs. membranous sst2, whereas untreated patients had exclusively membranous sst2. The internalized sst2 receptor corresponded to a single sst2 band in immunoblots and to sst2 receptors in in vitro receptor autoradiography. Although generally found in endosome-like structures, internalized sst2 receptors were also identified to a small extent in lysosomes, as seen in colocalization experiments. Conclusion: It is the first evidence showing that sst2 receptors can be internalized in sst2-expressing neuroendocrine tumors in patients under octreotide therapy, providing clues about sst2 receptor biology and trafficking dynamics in patients.

scholarly journals Targeted Chemotherapy Using a Cytotoxic Somatostatin Conjugate to Inhibit Tumor Growth and Metastasis in Nude Mice

2008 ◽  
Vol 2 ◽  
pp. CMO.S970 ◽  
Author(s):  
Li-Chun Sun ◽  
L. Vienna Mackey ◽  
Jing Luo ◽  
Joseph A. Fuselier ◽  
David H. Coy
Keyword(s):  
Drug Delivery ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Inhibitory Activity ◽  
Somatostatin Receptor ◽  
Receptor Subtype ◽  
Tumor Growth And Metastasis ◽  
Somatostatin Receptor Subtype 2

The major problems of traditional chemotherapy are non-selectivity and non-specificity, resulting in severe toxic side effects. Peptides are a new-generation of drug-delivery vector to increase efficacy of this therapy and avoid the resulting damage. The cytotoxic somatostatin (SST) conjugate JF-10-81 was developed by coupling camptothecin (CPT) to the N-terminus of a SST analog (JF-07-69) using an activated carbamate linker. This conjugate selectively targets somatostatin receptor subtype 2 (SSTR2) and also retains high binding affinity and rapid internalization as well as anti-proliferative activity towards various tumor cells. JF-10-81 was tested for its inhibitory activity against the growth of human tumors which included neuroblastoma (IMR32), pancreatic cancer (CFPAC-1), leukemia (MOLT-4), pancreatic carcinoid (BON) and prostate cancer (PC-3). Both SSTR2 mRNAs and proteins were detected in all these tumor cell lines. The conjugate displayed potent in vivo inhibitory activity, although some of the potency measured in in vitro experiments was lost. JF-10-81 was found to significantly inhibit growth of these SSTR-positive tumors, resulting in 87% tumor reduction in neuroblastoma IMR32 and 97% in leukemia MOLT-4 bearing animals, even inducing regression of CFPAC-1 tumors. SSTR-overexpressing BON tumors were unfortunately relatively CPT-insensitive in vitro, however, JF-10-81 again exhibited in vivo potency presumably by specifically increasing CPT concentrations inside the tumor cells so that the inhibition rate for JF-10-81 was 85%. Also, JF-10-81 was used to treat highly invasive PC-3 tumors where s.c. injections inhibited both tumor growth (almost 60% reduction) and tumor metastasis (over 70%). This conjugate demonstrated its broad and excellent anti-tumor activity by targeting SSTR2-specific tumor tissues, supporting that short peptides and their analogs may be applied as ideal drug-delivery carriers to improve the traditional chemotherapy.

scholarly journals A new 68Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Rosalba Mansi ◽  
Karim Abid ◽  
Guillaume P. Nicolas ◽  
Luigi Del Pozzo ◽  
Eric Grouzmann ◽  
...  
Keyword(s):  
Amino Acids ◽  
Somatostatin Receptor ◽  
Somatostatin Analog ◽  
Receptor Subtype ◽  
Somatostatin Receptor Subtype 2

scholarly journals Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney

2007 ◽  
Vol 34 (11) ◽  
pp. 1854-1860 ◽  
Author(s):  
Edgar J. Rolleman ◽  
Peter P. M. Kooij ◽  
Wouter W. de Herder ◽  
Roelf Valkema ◽  
Eric P. Krenning ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Human Kidney ◽  
Somatostatin Analogues ◽  
Receptor Subtype ◽  
Somatostatin Receptor Subtype 2

scholarly journals Ghrelin Receptor (GHS-R1a) and Its Constitutive Activity in Somatotroph Adenomas: A New Co-targeting Therapy Using GHS-R1a Inverse Agonists and Somatostatin Analogs

2014 ◽  
Vol 99 (12) ◽  
pp. E2463-E2471 ◽  
Author(s):  
Yves Mear ◽  
Marie-Pierre Blanchard ◽  
Céline Defilles ◽  
Thierry Brue ◽  
Dominique Figarella-Branger ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Inverse Agonist ◽  
Receptor Subtype ◽  
Dependent Manner ◽  
Constitutive Activity ◽  
Targeting Therapy ◽  
Ghrelin Receptor ◽  
Gh Secretion

Context: The ghrelin receptor GHS-R1a is highly expressed in human somatotroph adenomas and exhibits unusually high basal signaling activity. In humans, the suppression of this constitutive activity by mutation induces a short stature. Objective: Using a GHS-R1a inverse agonist, modified substance P (MSP), we explored the role of GHS-R1a constitutive activity in GH hypersecretion from somatotroph adenomas and as a putative therapeutic target. Design: The effects of MSP were assessed on GH secretion from 19 human somatotroph tumors in vitro. Moreover, these effects were compared with those of octreotide (somatostatin receptor subtype 2 [sst2] agonist) and with the combination of both drugs. Expression and localization of GHS-R1a and sst2 were studied. Results: For all tumors, MSP inhibited GH secretion in a dose-dependent manner from 13 to 64%. Moreover, MSP enhanced octreotide-induced GH inhibition. For five tumors, the effects of combined MSP plus octreotide treatment were significantly higher than the sum of effects of each drug alone. MSP increased the membrane localization of GHS-R1a and of microdomains colocalizing sst2-GHS-R1a, highlighting the cooperation between the two drugs. Conclusions: The GHS-R1a inverse agonist could open new therapeutic options for acromegalic patients, particularly patients partially sensitive to octreotide whose GH secretion is not completely controlled by the sst2 agonist.

scholarly journals Evans Blue Attachment Enhances Somatostatin Receptor Subtype-2 Imaging and Radiotherapy

Theranostics ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 735-745 ◽  
Author(s):  
Rui Tian ◽  
Orit Jacobson ◽  
Gang Niu ◽  
Dale O. Kiesewetter ◽  
Zhantong Wang ◽  
...  
Keyword(s):  
Evans Blue ◽  
Somatostatin Receptor ◽  
Receptor Subtype ◽  
Somatostatin Receptor Subtype 2
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