Identification of a unique ligand which has high affinity for all four bombesin receptor subtypes

Pradhan, Tapas K.; Katsuno, Tatsuro; Taylor, John E.; Kim, Sun H.; Ryan, Richard R.; Mantey, Samuel A.; Donohue, Patrick J.; Weber, H. Christian; Sainz, Eduardo; Battey, James F.; Coy, David H.; Jensen, Robert T.

doi:10.1016/s0014-2999(97)01527-6

Cited by 97 publications

(111 citation statements)

References 29 publications

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“…As a first example, we describe the effect of PA coinjection on the stability and localization of [ 111 In-DOTA-Ala 1 ]SS14 ( 111 In-DOTA-Ala-Gly-c[Cys-LysAsn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH) in somatostatin subtype 2 receptor (sst 2 )-expressing AR4-2J tumors in mice (16). Our second example involves the bombesin analog 111 In-PanSB1 ([ 111 In-DOTA-PEG 2 -DTyr-Gln-Trp-Ala-Val-bAla-His-Phe-Nle-NH 2 ), which is based on a previously reported sequence exhibiting a pan-bombesin receptor binding profile (17)(18)(19). The effect of PA on in vivo stability and tumor uptake was studied and assessed with human PC-3 xenografts expressing the gastrinreleasing peptide receptor (GRPR) in mice (20,21).…”

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confidence: 99%

“To Serve and Protect”: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting

et al. 2013

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Radiolabeled octreotide analogs are most successfully being applied today in clinical cancer imaging and treatment. Propagation of this paradigm to other radiopeptide families has been greatly hampered by the inherent poor metabolic stability of systemically administered peptide analogs. We hypothesized that the in vivo coadministration of specific enzyme inhibitors would improve peptide bioavailability and hence tumor uptake. Through single coinjection of the neutral endopeptidase inhibitor phosphoramidon (PA), we were able to provoke remarkable rises in the percentages of circulating intact somatostatin, gastrin, and bombesin radiopeptides in mouse models, resulting in a remarkable increase in uptake in tumor xenografts in mice. Methods: The peptide conjugates [DOTA-Ala 1 ]SS14 (DOTA-Ala-Gly-c[Cys-LysAsn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH), PanSB1 (DOTA-PEG 2 -DTyr-Gln-Trp-Ala-Val-bAla-His-Phe-Nle-NH 2 ), and DOTA-MG11 (DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 ) were labeled with 111 In by 20 min of heating at an acidic pH. Metabolic stability was studied with high-performance liquid chromatography analysis of blood samples collected 5 min after the injection of the test radiopeptide alone or with PA into mice. Biodistribution was studied after injection of each 111 In-labeled radiopeptide alone or after coinjection of PA in tumor-bearing severe combined immunodeficient (SCID) mice. Results: The amount of intact [ 111 In-DOTA-Ala 1 ] SS14 detected in the mouse circulation at 5 min after the injection of PA increased impressively-from less than 2% to 86%-whereas the uptake in AR4-2J xenografts rose from less than 1 percentage injected dose per gram of tissue (%ID/g) to 14 %ID/g at 4 h after injection. Likewise, the coadministration of PA resulted in a marked increase in the amount of circulating intact 111 In-PanSB1-from 12% to 80%-at 5 min after injection, and radioligand uptake in human PC-3 xenografts in SCID mice escalated from less than 4 %ID/g to greater than 21 %ID/g at 4 h after injection. In a similar manner, the coadministration of PA resulted in an equally impressive increase in intact [ 111 In-DOTA]MG11 levels in the mouse bloodstream-from less than 5% to 70%-at 5 min after injection, leading to a remarkable increase in radiotracer uptake-from 2 %ID/g to greater than 15 %ID/g-in both AR4-2J tumors and A431(CCKR1) tumors (i.e., tumors induced by A431 cells transfected to stably express the human cholecystokinin subtype 2 receptor) in mice at 4 h after injection. This effect was well visualized by SPECT/CT imaging of AR4-2J tumor-bearing mice at 4 h after injection. Conclusion: The results of this study clearly demonstrate that the coadministration of key enzyme inhibitors can effectively prolong the survival of radiolabeled peptides in the circulation, securing their safe transit to the target. This strategy clearly provoked an unprecedented increase in radiolabel accumulation in tumor xenografts in mice; this increase might translate into higher diagnostic sensitivity or improved therapeutic...

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confidence: 99%

“To Serve and Protect”: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting

et al. 2013

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“…The peptide analog [D-Tyr6, β-Ala11, Phe13, Nle14]bombesin-(6-14) is a universal bombesin ligand, which has been shown to bind to all four GRP receptor sub-types with high affinity (Mantey et al 1997;Pradhan et al 1998;Van de Wiele et al 2000). The GRP family of receptors are known to be over-expressed in a variety of human tumors, including prostate cancer, making the pan-bombesin peptide a potentially important targeting entity for both cancer diagnosis and treatment (Patel et al 2006;Sun et al 2000).…”

Section: Peptide Synthesismentioning

confidence: 99%

“…Radionuclide probes based on bombesin, an amphibian tetradecapeptide, have been reported to specifically target GRP overexpressing tumors (Hoffman et al 2003;Van de Wiele et al 2000). Four different receptor sub-types were discovered for the GRP family of peptides: GRP-R, neuromedin-B receptor (NMB-R), BRS-3, and BB4-R. A very potent ligand for all four bombesin receptor sub-types was previously reported, with a structure of [D-Tyr6, β-Ala11, Phe13, Nle14]bombesin-(6-14) (Mantey et al 1997;Pradhan et al 1998;Reubi et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of bombesin-functionalized iron oxide nanoparticles and their specific uptake in prostate cancer cells

et al. 2009

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The imaging of molecular markers associated with disease offers the possibility for earlier detection and improved treatment monitoring. Receptors for gastrin-releasing peptide are overexpressed on prostate cancer cells offering a promising imaging target, and analogs of bombesin, an amphibian tetradecapeptide have been previously demonstrated to target these receptors. Therefore, the pan-bombesin analog [β-Ala11, Phe13, Nle14]bombesin-(7-14) was conjugated through a linker to dye-functionalized superparamagnetic iron oxide nanoparticles for the development of a new potential magnetic resonance imaging probe. The peptide was conjugated via click chemistry, demonstrating a complementary alternative methodology to CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript conventional peptide-nanoparticle conjugation strategies. The peptide-functionalized nanoparticles were then demonstrated to be selectively taken up by PC-3 prostate cancer cells relative to unfunctionalized nanoparticles and this uptake was inhibited by the presence of free peptide, confirming the specificity of the interaction. This study suggests that these nanoparticles have the potential to serve as magnetic resonance imaging probes for the detection of prostate cancer.

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“…CHO-K1 cells lacking expression of endogenous BN-like peptide receptors (Katsuno et al, 1999) were transfected with chGRP-R or chBRS-3.5 expression vector using lipofection, and G418-resistant colonies were expanded. To select transfected cell lines expressing high levels of receptors, clones were screened by comparing their ability to bind 40 pM [ (6 -14), which has high affinity for rat GRP-R, rat NMB-R, human BRS-3 as well as for frog BB4 (Pradhan et al, 1998 bound to both chGRP-R and chBRS-3.5 in a saturable manner. In the presence of 1 mM of non-radiolabeled ligand, only nonspecific binding was observed, which was proportional to the ligand concentration and lower than 10% of the total binding.…”

Section: Functional Analysis Of Chbn-rmentioning

confidence: 99%

“…For example, rat pancreatic acinar cells expressing GRP-R show a K i value of 0.99 nM for [FAFNl]BN(6 -14) (Pradhan et al, 1998), mouse GRP-R-transfected BALB3T3 has K i values of 0.9 and 3.1 nM for BN and GRP, respectively (Benya et al, 1994), and these values for human GRP-R transfected BALB3T3 are 1.4 and 6.2 . ChGRP-R was distributed in the brain and GI tissue, which is a common feature of GRP-R of mammals, amphibians and Aves Nagalla et al, 1995).…”

Section: Iwabuchi Et Almentioning

confidence: 99%

Molecular cloning and characterization of avian bombesin‐like peptide receptors: new tools for investigating molecular basis for ligand selectivity

Iwabuchi

Ui-Tei

Yamada

et al. 2003

British J Pharmacology

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1 Bombesin (BN), originally isolated from amphibians, is structurally related to a family of BN-like peptides found in mammals, which include gastrin-releasing peptide (GRP) and neuromedin B (NMB). These peptides have important effects on secretion, smooth muscle contraction, metabolism and behavior. Here we report cloning and characterization of two subtypes of BN-like peptide receptors in Aves. 2 The amino-acid sequence of chick GRP-R (chGRP-R) is highly identical with mammalian and amphibian GRP-R, and this receptor showed high affinity for GRP, BN (6 -14)). The chGRP-R gene was localized to chicken chromosome 1q23distal-q24proximal, where chick homologs of other human Xlinked genes have also been mapped. 3 ChBRS-3.5, having sequence similarities to both mammalian bombesin-like peptide receptor subtype-3 and amphibian bombesin-like peptide receptor subtype-4, showed high affinity for [FAFNl]BN(6 -14), moderate affinity for BN, but low affinity for both GRP and NMB. 4 Expression of both receptors was detected in brain, but only chGRP-R was expressed in gastrointestinal (GI) tissues. 5 When expressed in Chinese hamster ovary K1 cells, these receptors mediate intracellular calcium mobilization upon agonist stimulation. These results suggest that a novel BN peptide may occur in Aves as an endogenous ligand for chBRS-3.5. 6 The receptor sequences responsible for ligand selectivities were discussed and this knowledge about avian BN-like peptide receptors will help us to understand the molecular basis for agonist sensitivities of BN-like peptide receptors.

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Identification of a unique ligand which has high affinity for all four bombesin receptor subtypes

Cited by 97 publications

References 29 publications

“To Serve and Protect”: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting

“To Serve and Protect”: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting

Synthesis of bombesin-functionalized iron oxide nanoparticles and their specific uptake in prostate cancer cells

Molecular cloning and characterization of avian bombesin‐like peptide receptors: new tools for investigating molecular basis for ligand selectivity

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