The metabolism of BW2258U89, a GRP receptor antagonist

Márquez, César; Treston, Anthony M.; Moody, Elizabeth; Jakowlew, Sonia B.; Moody, Terry W.

doi:10.1054/npep.2000.0798

Cited by 9 publications

(6 citation statements)

References 28 publications

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“…Bombesin/GRP is a recognized growth factor for SCLC and the effectiveness of their antagonists for the in vivo treatment of experimental human SCLC has been well documented (2,(5)(6)(7)(8)(9)11). In contrast, much less is known about the involvement of bombesin/GRP antagonistic analogues in the regulation of NSCLC (38,39), and the possible therapeutic benefits of bombesin/GRP antagonists for the therapy of NSCLC have not been evaluated in studies in vivo. Similarly, our GHRH antagonists strongly suppress the growth of various experimental cancers such as lung, osteosarcomas, glioblastomas, pancreatic, colorectal, breast and ovarian tumors (11).…”

Section: Discussionmentioning

confidence: 99%

Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer

Kanashiro

Zarándi²,

Hammann³

et al. 2007

Int J Oncol

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New therapeutic strategies are necessary to improve the treatment of lung cancer. We investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonist, RC-3940-II, and growth hormone-releasing hormone (GHRH) antagonists, MZ-J-7-114 and MZ-J-7-118, on the expression of epidermal growth factor receptor (EGFR)/HER (-2,-3, and-4) family, angiogenic factors, VEGF-A and VEGF receptors (VEGF-R1 and VEGF-R2), and the apoptotic molecules Bax and Bcl-2, in H-460 and A-549 non-small cell lung carcinomas (NSCLC). Nude mice bearing xenografts of H-460 and A-549 NSCLC were treated daily with these peptide analogues for 4 weeks. The treatment resulted in growth inhibition of H-460 by 22-77% and A-549 NSCLCs by 64-84%. The inhibition of tumor growth was associated with a down-regulation of members of EGFR/HER family. A significant reduction of the levels of expression of EGFR/ HER family on both tumors varied from 29-96%: the greatest inhibition being induced by RC-3940-II. Similarly, a significant decrease in the levels of VEGF-A in tumors by 19-60% and VEGF receptors (VEGF-R1, 24-74% and VEGF-R2, 25-50%) was detected after therapy. An up-regulation of Bax by 21-63% and a down-regulation of Bcl-2 by 23-39% was observed only for H-460 NSCLC. Our study demonstrates that human H-460 and A-549 NSCLC, express receptors for GHRH and bombesin/GRP, and respond to the respective antagonists. The antagonists of bombesin/GRP and GHRH could provide a new strategy for treatment of NSCLC through downregulation of EGFR/HER family and an interference with the angiogenic and apoptotic pathways.

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Section: Discussionmentioning

confidence: 99%

Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer

Kanashiro

Zarándi²,

Hammann³

et al. 2007

Int J Oncol

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“…GRP, which has an identical heptapeptide COOH terminus to Bn (Bunnett, 1994), has a half-life of only 1.4 min in the circulation in the pig (Knuhtsen et al, 1984) and Ͻ5 min in mouse plasma (Marquez et al, 2000) while being degraded primarily by cleavage at the His 12 -Leu 13 peptide bond and also at the Trp 8 -Ala 9 peptide bond at the COOH terminus (Shipp et al, 1991). CPT-L2-BA3 had a half-life of 30 min in mouse plasma, which exceeded the value for GRP of Ͻ5 min, demonstrating its enhanced stability in plasma.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and in Vivo Antitumor Effects of Cytotoxic Camptothecin-Bombesin Conjugates Are Mediated by Specific Interaction with Cellular Bombesin Receptors

Moody¹,

Sun²,

Mantey³

et al. 2006

J Pharmacol Exp Ther

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Most human tumors overexpress or ectopically express peptide hormone/neurotransmitter receptors, which are being increasingly studied as a means to selectively deliver cytotoxic agents. Although a number of peptide ligand-constructs demonstrate tumor cytotoxicity, the role of specific tumoral receptor interaction in its mediation is unclear. To address this question, we synthesized camptothecin (CPT) bombesin (Bn) analogs, in which CPT was coupled via a novel carbamate linker, L2 [N-(Nmethyl-amino-ethyl)-glycine carbamate], that were chemically similar but differed markedly in their potency/affinity for human Bn receptors. We then examined their ability to interact with Bn receptors and cause in vitro and in vivo tumor cytotoxicity.

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“…2.4 Synthesis and purification of [Asn 3 , Lys 6 , Thr 10 , Phe 13 ]3-14-bombesin and [Asn 3 , Lys 6 , Phe 13 ]3-14-bombesin [Asn 3 , Lys 6 , Thr 10 , Phe 13 ]3-14-bombesin and [Asn 3 , Lys 6 , Phe 13 ] 3-14-bombesin were synthesized by using the solid-phase peptide synthesis technique through an automated solid phase 2-channel peptide synthesizer (Tribute ® , Gyros Protein Technologies, United States) along with Rink Amide MBHA resin (100-200 mesh) and Fmoc chemistry. An optimized cleavage cocktail was developed for removing the peptides from resin and side chain-protecting groups as described elsewhere (Marquez et al, 2000). The synthetic peptides were lyophilized instantly after being washed using cold diethyl ether.…”

Section: Fractionation Of Frog Skin Secretion and Peptide Sequencingmentioning

confidence: 99%

Two novel bombesin-like neuropeptides from the skin secretion of Pelophylax kl. esculentus: Ex vivo pharmacological characterization on rat smooth muscle types

Zhang

Chen²,

Zou³

et al. 2022

Front. Mol. Biosci.

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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, [Asn3, Lys6, Thr10, Phe13]3–14-bombesin and [Asn3, Lys6, Phe13]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 EC50 values in the range of 22.64 ± 9.7 nM (N = 8) to 83.93 ± 46.9 nM (N = 8). The potency of [Asn3, Lys6, Thr10, Phe13]3–14-bombesin was approximately 3-fold higher than that of [Asn3, Lys6, Phe13]3–14-bombesin. Through the investigation of receptor selectivity using a canonical bombesin receptor antagonist, it was found that [Asn3, Lys6, Thr10, Phe13]3–14-bombesin and [Asn3, Lys6, Phe13]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, [Asn3, Lys6, Thr10, Phe13]3–14-bombesin and [Asn3, Lys6, Phe13]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.

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The metabolism of BW2258U89, a GRP receptor antagonist

Cited by 9 publications

References 28 publications

Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer

Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer

In Vitro and in Vivo Antitumor Effects of Cytotoxic Camptothecin-Bombesin Conjugates Are Mediated by Specific Interaction with Cellular Bombesin Receptors

Two novel bombesin-like neuropeptides from the skin secretion of Pelophylax kl. esculentus: Ex vivo pharmacological characterization on rat smooth muscle types

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