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Competition curves in representative samples of myometrium, a leiomyoma, and peritumoral vessels from an endometrial carcinoma using 125 I-Tyr 4 -bombesin as radioligand. Successive tissue sections were incubated with the radioligand and increasing concentrations of unlabeled GRP (F), NMB (OE), and 1000 nmol/liter somatostatin (SS-14) (f). High-affinity displacement of the tracer is found with GRP, whereas NMB induces only displacement at lower affinity. Somatostatin has no effect. Nonspecific binding was subtracted from all values. The observed rank order of potencies of these analogs is compatible with the GRP-R subtype.
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Bombesin-like neuropeptides including gastrin-releasing peptide (GRP) and their corresponding receptors, mediate multiple physiological actions and have biological significance in cancer. However, information about the function of these neuropeptides and the incidence, distribution, density, and subtype of their receptors in human uterine tissues i...
Context in source publication
Context 1
... was obtained by the labeling of the normal and neoplastic tissues with the GRP-R-preferring radioligand 125 I-Tyr 4 -bombesin (Figs. 1, 3, and 4); by competition exper- iments using 125 I-Tyr 4 -bombesin demonstrating a strong af- finity of the receptors for GRP but a weaker affinity for NMB, as shown by the complete displacement curves in Fig. 5 in three different tissues, namely myometrium, leiomyoma, 13 , Nle 14 -bomb- esin (6 -14), showing that it was well displaced by nanomolar concentrations of d-Tyr 6 , -Ala 11 , Phe 13 , Nle 14 -bombesin (6 - 14) and of GRP but only poorly with NMB (Fig. 2, ...
Citations
... Most of the therapeutic approaches rely on radiopharmaceuticals, which are composed of conjugated or unconjugated radionuclides. The conjugation allows for localization, and accumulation in specific tumour sites should the radionuclide be Table 1 Overview of peptide with receptors overexpressed in tumours Peptide Tumour expression References Somatostatin Neuroendocrine tumour (gastroenteropancreatic tumour, pituitary tumour), lymphomas, carcinoids, paragangliomas, breast, brain, small cell lung cancer Reubi (2003Reubi ( , 2004, Reubi and Waser (2003), and Rufini et al. (2006) Bombesin Prostate, breast, pancreas, gastric, small cell lung cancer, colorectal cancer Reubi (2003Reubi ( , 2004 and Fleischmann et al. (2005) ...
Targeted alpha therapy (TAT) has emerged as a viable therapeutic option for cancer management, due to its high target specificity and superlative ability to effectively disrupt the genetic make-up of the cancerous cells, thereby impeding their aggressive growth. TAT belongs to the category of radioligand therapies in oncology wherein alpha-emitting radionuclides are delivered directly to tumours and the tumour microenvironment with little impact on surrounding healthy cells. This approach is facilitated by chelating the radionuclides with ligands or conjugating them to targeting vehicles which facilitate their biodistribution, localization, and accumulation in the target sites. Currently, TAT continues to exhibit promising therapeutic outcomes in both preclinical and clinical evaluations, with more exciting prospects for the future. Accordingly, this timely review focuses on the pertinent, appealing merits of TAT, elaborating on the favourable chemical properties of potent alpha-emitting radionuclides and their enhancement. The current review also delves into the radiobiology and dosimetry of alpha-particles, and their application to TAT. Recent preclinical and clinical reports have further supported the viability of TAT as a promising therapeutic intervention. More so, this review sheds light on the promising therapeutic possibilities that nuclear medicine, particularly TAT, can offer in oncology.
... This phenomenon implies that a single species may contain diverse molecules that most likely result from the associated effects of gene mutations and duplications. As the universal occurrence of neuropeptides in the frog skin was considered to participate in skin defensive responses against predators (Davis et al., 1992) and different forms of BLPs might have varying half-life (Fleischmann et al., 2005), the frogs need more complicated cocktails in skin secretion that makes predators or pathogens more difficult to fight against them and protects them from attack or invasive microorganisms to some extent. ...
Mammalian bombesin-like neuropeptides (BLPs) play an important role in regulation of physiological and pathophysiological processes. Frog skin-derived BLPs, of smaller size and diverse lengths and sequences at their N-terminus, have attracted the attention of many researchers. However, these N-terminal variants and the receptors modulating their pharmacological actions are poorly studied and less understood. In this study, two BLPs, namely, [Asn ³ , Lys ⁶ , Thr ¹⁰ , Phe ¹³ ]3–14-bombesin and [Asn ³ , Lys ⁶ , Phe ¹³ ]3–14-bombesin with primary structures NLGKQWATGHFM and NLGKQWAVGHFM were isolated from the skin secretion of hybrid Pelophylax kl. esculentus . Both BLPs share a similar primary structure with only a single amino acid substitution at the eighth position (threonine to valine), while they have quite different myotropic potencies with EC 50 values in the range of 22.64 ± 9.7 nM ( N = 8) to 83.93 ± 46.9 nM ( N = 8). The potency of [Asn ³ , Lys ⁶ , Thr ¹⁰ , Phe ¹³ ]3–14-bombesin was approximately 3-fold higher than that of [Asn ³ , Lys ⁶ , Phe ¹³ ]3–14-bombesin. Through the investigation of receptor selectivity using a canonical bombesin receptor antagonist, it was found that [Asn ³ , Lys ⁶ , Thr ¹⁰ , Phe ¹³ ]3–14-bombesin and [Asn ³ , Lys ⁶ , Phe ¹³ ]3–14-bombesin had an affinity to both BB1 and BB2 receptors. Their contractile functions are mainly modulated by both BB1 and BB2 receptors on rat urinary bladder and BB2 alone on rat uterus smooth muscle preparations. These data may provide new insights into the design of potent and selective ligands for bombesin receptors. Moreover, [Asn ³ , Lys ⁶ , Thr ¹⁰ , Phe ¹³ ]3–14-bombesin and [Asn ³ , Lys ⁶ , Phe ¹³ ]3–14-bombesin did not induce significant hemolysis and toxicity in normal human cells, suggesting that these two natural novel BLPs have great potential for development into new drug candidates.
... The affinity of BB1 towards NMB is seen to be 100-fold higher than towards GRP. On the other hand, the affinity of BB2 receptor towards GRP is found to be 50fold higher than towards NMB [20,21]. ...
Peptides-coupled imaging agents are emerging as a new tool for early diagnosis with low adverse effects. Peptide-receptor based radiolabeled complex with good affinity to target specific receptors in cancers are required for imaging and quantification. Receptor mediated targeting of tumors for diagnosis, therapy or both is an encouraging approach and has increased remarkably over past 10-15 years. The attainment of these approaches related to selection of specific receptor for certain cancer type and their binding to the specific ligand. Receptor targeting radiopharmaceuticals are easy to synthesize and being small molecules, they exhibit excellent permeability, low immunogenicity, high specificity and minimum side effects. Gastrin-releasing three mammalian bombesin peptide receptors have shown great potential for cancer targeting because of their overexpression in various human malignancies. This review discusses the recent advances of bombesin receptors as potential targets for diagnosis using radiolabel bombesin analogues in prostate, lung, and breast cancer.
... The affinity of BB1 towards NMB is seen to be 100-fold higher than towards GRP. On the other hand, the affinity of BB2 receptor towards GRP is found to be 50fold higher than towards NMB [20,21]. ...
... The BB2 subtype is also known as the gastrin-releasing peptide receptor (GRPR), because the C-terminal region of Bn is homologous to the mammalian gastrin-releasing peptide (GRP) (Jensen et al., 2008). GRP is a modulatory neurotransmitter that also acts as an endocrine cancer cell-growth factor for normal tissues and neoplastic cells of various origins; it stimulates several physiological processes including exocrine secretion and smooth muscle contraction and has trophic effects (Fleischmann et al., 2005;Varvarigou et al., 2004). BB1 has more than 100-fold higher affinity towards NMB than GRP, whereas the BB2 receptor has approximately 50-fold higher affinity for GRP than NMB. ...
... Breast, prostate, lung, colon, glioblastoma, neuroblastoma, head, gastrointestinal, pancreatic, and neck squamous cell cancers (Fleischmann et al., 2005;Gugger and Reubi, 1999;Jensen et al., 2008;Markwalder and Reubi, 1999;Moody et al., 2004;Reubi et al., 2004;Uri et al., 2018) BB3 MK-50946 and Bantag-1 Regulation of blood glucose level, energy balance, weight control Testis, lung, neuroendocrine, pancreas, pituitary, ovarian, and prostate cancers (Moreno et al., 2013;Reubi et al., 2002) D. Pooja, et al. International Journal of Biochemistry and Cell Biology 114 (2019) 105567 head/neck squamous cell, ovarian, pancreatic, and prostate cancers, and neuroblastomas (Moody et al., 2004;Moreno et al., 2016;Pu et al., 2015) (Tables 1 and 2). ...
The biggest challenge in delivering anticancer agents is the ability to direct these molecules specifically to cancer cells. With this in mind, modern research is focussing on improving the precision of cancer drug delivery by incorporating a ligand that has the ability to specifically recognize cancer cells. Peptides are emerging as a new tool in drug and gene delivery. Peptide-drug conjugates, peptide-modified drug delivery systems, and peptide-coupled imaging agents have been shown to increase on-site delivery. This has allowed better tumor mass contouring in imaging and increased therapeutic efficacy of chemotherapies, reducing adverse effects. Benefits of peptide ligands include their small size, easy and affordable production, high specificity and remarkable flexibility regarding their sequence and conjugation possibilities. Bombesin (Bn) receptors have shown great promise for tumor targeting due to their increased expression in a variety of human cancers, including prostate, breast, small cell lung, and pancreatic cells. This review discusses the overexpression of Bn receptors in different cancers and various approaches to target these receptors for therapeutic and diagnostic interventions in human malignancies.
... One of the most often explored targets is the mammalian subtype 2 bombesin receptor, namely the gastrin releasing peptide receptor (GRPr). The wide expression of GRPr in prostate [2,3], breast cancer [2,4], but also in bladder [3], ovarian [5], and uterine cancer [6] represented the incentive for the development of GRPr-based radioligands, with the potential of being used in molecular diagnostics and therapy. In an attempt to generate radiotracers able to efficiently target GRPr and taking into account the favorable properties of GRPr-agonists, such as high tumor uptake via specific cellular internalization, numerous GRPr-based radioagonists were designed and underwent preclinical testing. ...
Methods:
The GRPr-antagonist (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) was functionalized with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via the spacer 4-amino-1-carboxymethyl-piperidine (Pip) and the amino acid N-Methyl-β-Ala, to obtain NMe-RM2 and labeled with (68)Ga and (177)Lu. The GRPr affinity of the corresponding metalloconjugates determined using [(125)I-Tyr(4)]-BN as radioligand. In vitro evaluation included internalization studies using PC3 cells. The (68)Ga-conjugate was evaluated in PC3 xenografts by biodistribution and PET studies, while investigations on the metabolic stability and plasma protein binding were performed.
Results:
The half maximum inhibitory concentrations (IC50) of the metalloconjugates, using [(125)I-Tyr(4)]-BN, are in the low nanomolar range. PC3-cell culture binding studies of both metallated NMe-RM2 and RM2 show high GRPr-bound activity and low internalization. Metabolic studies showed that (68)Ga-NMe-RM2 and (68)Ga-RM2 are being cleaved in a similar fashion into three metabolites, with a good proportion of about 50% of the remaining blood activity at 15min post injection (p.i.) being represented by the intact radiotracer. (68)Ga-NMe-RM2 was shown to target specifically PC3 xenografts, with high and sustained tumor uptake of about 13% IA/g within a time frame of 3h. The PET images clearly visualized the tumor.
Conclusions:
The relatively high percentage of the remaining intact radiotracer in blood 15min post injection sufficiently enables in vivo targeting of GRPr positive tumors, finding which has been also shown in clinical trials.
... The presence of these signaling molecules are therefore used as a marker of tumor aggressiveness and of reduced survival chances; thus, it is promising target for SCLC treatment [15][16][17][18]. The activation of GRP/BN-GRPR pairs has been demonstrated in many other cancer types, including breast and ovarian cancers [19][20][21], prostate cancer [22,23], gastrointestinal tract tumors [24][25][26], colon cancer [27,28], pancreatic cancers [29,30], where it has also been proposed as a radiological marker to distinguish pancreatitis from ductal pancreatic carcinoma [31], head and neck squamous cell carcinomas [32], glioblastoma [33], neuroblastomas [34], uterine [35] and renal cancer [36,37] (Table 1). ...
... SCLC [15][16][17][18] Breast [19][20] Ovarian [21] Prostate [22][23] Gastrointestinal [24][25][26] Colon [27][28] Pancreatic [29][30][31] Head and neck [32] Glioblastoma [33] Neuroblastoma [34] Uterine [35] Renal [36][37] Antisense oligonucleotides GRPR-ASOs [85] GRPR is also an attractive target for radionuclide therapy; therefore, several labeled antagonists have been devel-oped and tested in cancer diagnosis as well as in therapy. RM2 (BAY1017858), a novel 177Lu-labeled GRPR antagonist, was recently tested in prostate cancer both alone and in combination with rapamycin treatment, resulting in a high tumor uptake and a rapid clearance from normal organs [49,50]. ...
Growth factors of the bombesin/gastrin releasing peptide (BN/GRP) family play a critical role in proliferation and progression of many malignancies. Many inhibitors targeting GRP signalling have been developed and tested as anticancer compounds showing promising preclinical and early phase clinical results. In this review we will discuss the molecular signalling, the expression and the functional role of BN/GRP-GRPR in different cancer models and will focus on the available strategies to target BN/GRP-GRPR in cancer treatment as well as in tumour diagnosis and follow up.
... The GRPR is also expressed in the neoplastic cells of renal cell carcinoma, breast cancer, lung cancer, colon cancer, gastrinoma, endometrial cancer and gastrointestinal stromal tumours. 36,[53][54][55][56][57][58] Other cancers, such as ovarian and pancreatic cancers, express GRPR in their tumoral vessels. 22 The expression of GRPR in renal cell carcinoma tumour cells has been demonstrated by PCR, binding assays, immunohistochemistry and receptor autoradiography. ...
Gastrin releasing peptide (GRP) is a regulatory peptide that acts through its receptor (GRPR) to regulate physiological functions in various organs. GRPR is overexpressed in neoplastic cells of most prostate cancers and some renal cell cancers and in the tumoral vessels of urinary tract cancers. Thus, targeting these tumours with specifically designed GRP analogues has potential clinical application. Potent and specific radioactive, cytotoxic or nonradioactive GRP analogues have been designed and tested in various animal tumour models with the aim of receptor targeting for tumour diagnosis or therapy. All three categories of compound were found suitable for tumour targeting in animal models. The cytotoxic and nonradioactive GRP analogues have not yet shown convincing tumour-reducing effects in human trials; however, the first clinical studies of radioactive GRP analogues-both agonists and antagonists-suggest promising opportunities for both diagnostic tumour imaging and radiotherapy of prostate and other GRPR-expressing cancers.
... La bombesina (BN) es un tetradecapéptido aislado de la piel de batracios que presenta la secuencia (pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 ) y muestra gran afinidad por los receptores del péptido liberador de la gastrina (PLG) 4,7 . Dichos receptores se sobre-expresan en el cáncer pulmonar de células pequeñas o adenoides, en tumores malignos de próstata, en el carcinoma medular de tiroides, en los melanomas, las neoplasias malignas de mamas, en el cáncer gastrointestinal, de colon, duodenal, de páncreas, en algunas neoplasias uterinas, así como en el hipotálamo y en la hipófisis 4,8,10,11 . Se ha demostrado, recientemente, que el 99m Tc-N 2 S 2 -Tat-(49-57) BN, fragmento de la molécula nativa, es capaz de internalizarse en el núcleo de células malignas de mamas y de próstata, lo cual lo hace ser un agente prometedor para la terapia 12 de dichos tumores. ...
The aim of present investigation was to evaluate biodistribution in healthy animals and in tumor models of the radiopharmaceuticals (99m)Tc-EDDA/tricine-HYNIC-Lys3-Bombesin (HYNIC-Lys3-BN) and (99m)Tc-NA/tricine-HYNIC-Lys3-BN. Biodistribution and pharmacokinetics were carried out over 24 hours. To do so, 24 healthy Wistar rats were used and were administered 37.0 ± 0.8 MBq/rat of each radiopharmaceutical. For the tumor model study, 20 CD-1 nude mice were used and prostate tumors (PC3) were implanted in all the mice. Ten days later, tumor volumes were calculated and 40.00 ± 0.04 MBq/mice of each radiopharmaceutical were injected. Both showed high radiochemical purity: 98.08 ± 0.25% for EDDA/tricine product and 95.1 ± 0.3% for the conjugate with NA/tricine. Uptake of the radiopharmaceutical with NA/tricine was significantly higher in organs of the reticulo-endothelial system of healthy Wistar rats during 24h, specifically in the liver and spleen. Both labeled compounds showed no significant differences between their blood elimination half lives. Average of tumor growth was 0.93 ± 0.02 cm(3) and affinity for tumors showed a growing and specific binding of both radiopharmaceuticals, although it was significantly higher for the EDDA/tricine conjugate. This outcome made it possible to corroborate the direct relationship between the density of gastrin releasing peptide and its receptors (GRPr) and the variation of the accumulation of the radiopharmaceuticals in the tumor. Use of EDDA/tricine as coligand is more appropriate than NA/tricine for labeling of HYNIC-Lys3-BN with (99m)Tc.
Copyright © 2011 Elsevier España, S.L. y SEMNIM. All rights reserved.
... BN-like peptides mediate their action by binding to G-protein-coupled receptors [2,4]. The BN family of receptors includes four different receptor subtypes: the neuromedin B receptor (BB1), the GRP receptor (BB2), the orphan BN receptor (BB3) and the amphibian BN receptor (BB4) [3][4][5][6]. BN has been shown to have high affinity for GRP receptor [2]. Overexpression of receptors for both BN and GRP on several malignant tumors and relatively low expression in normal tissues make BN/GRP receptor a potential molecular target for targeting cancer with radiolabeled BN peptides. ...
... Most of the BN-like peptides that have been designed and developed for tumor targeting are based on the GRP receptor specific motif (Gln 7 -Trp 8 -Ala 9 -Val 10 -Gly 11 -His 12 -Leu 13 -Met 14 -NH 2 ). The recent discovery of a potent universal ligand (D-Tyr 6 -Gln 7 -Trp 8 -Ala 9 -Val 10 -βAla 11 -His 12 -Phe 13 -Nle 14 ), BNU (6)(7)(8)(9)(10)(11)(12)(13)(14), which is known to bind to all the four BN receptor subtypes, is an important step towards the development of effective BN peptides capable of targeting different BN receptor-expressing tumors having different BN receptor subclasses [12,13]. Many reports on BN peptides based on normal sequence have been published in recent years [1,7], as opposed to the few reports on radiopeptides derived from the universal BN sequence [3,14]. ...
... In this study, we designed several biologically active minimal sequence of BN peptides derived from normal or the universal sequence in order to find out peptide structure-pharmacologic relationship for achieving optimal pharmacokinetics and tumor targeting. Besides the advantage of using the 6-14 amino acid sequence truncated from 14-amino-acid BN peptide for easy preparation and handling, we compared the biological and tumor targeting properties of the newly synthesized BN (6)(7)(8)(9)(10)(11)(12)(13)(14) peptides with the full-sequence BN peptide in order to evaluate their potential as tumor imaging agents. ...
Among the many clinically relevant peptide receptor systems, bombesin (BN) receptors have attracted enormous attraction due to their overexpression in various frequently occurring human tumors including breast and prostate, thus making such receptors promising targets with radiolabeled BN analogs. The present study describes the preparation and evaluation of a series of new BN derivatives as potential tumor imaging agents.
Several new BN derivatives with the common structure MAG(3)-X-BN(1-14 or 6-14), where X=Asp or Asp-Asp, were synthesized by solid-phase peptide synthesis. S-benzoylmercaptoacetic acid was incorporated at the end of synthesis via manual conjugation to yield MAG(3)-BN conjugates. Radiolabeling with (99m)Tc was accomplished by ligand exchange method. The receptor-binding affinity assays were performed in MDA-MB-231, MCF-7, T47-D and PC-3 cancer cell lines. In vivo biodistribution and clearance kinetics were assessed in Balb/c mice, and tumor targeting efficacy was determined in nude mice bearing breast tumor xenografts.
The peptides were prepared conveniently and radiolabeled efficiently with (99m)Tc (up to 95% labeling efficiency). In vitro cell binding assays demonstrated high affinity (values in the nanomolar range) of (99m)Tc peptides towards breast and prostate cancer cell lines. In addition, the radioconjugates displayed significant internalization (values ranged between 19% and 35%) in tumor cells. In vivo biodistribution and biokinetics are characterized by efficient clearance from the blood and variable degrees of excretion through the renal pathway. In vivo tumor targeting studies displayed variable uptake capacity of different BN derivatives, underlining the influence of specific amino acid sequence on tumor targeting profiles. Tumor uptake was always higher than the radioactivity in the blood and muscle, with good tumor retention and good tumor-to-blood and tumor-to-muscle ratios, indicating the potential of these agents for targeting tumors in vivo.
The combination of favorable in vitro and in vivo properties may render these BN peptides as potential candidates for targeting BN/GRP receptor-positive tumors. They deserve further evaluation to determine their real strength. The present data indeed provide useful information regarding peptide structure-pharmacologic activity relationship, which might be useful in designing and developing new BN-like peptides for efficient targeting of tumors in vivo.
