HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jnumed.107.045054v1 49/2/318    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cescato, R. Articles by Reubi, J. C. Search for Related Content PubMed PubMed Citation Articles by Cescato, R. Articles by Reubi, J. C.

Bombesin Receptor Antagonists May Be Preferable to Agonists for Tumor Targeting

¹ Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland; and ² Molecular Radiopharmacy Section, Institute of Radioisotopes–Radiodiagnostic Products, National Center for Scientific Research Demokritos, Athens, Greece

Correspondence: For correspondence or reprints contact: Jean Claude Reubi, MD, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, P.O. Box 62, Murtenstrasse 31, CH-3010 Berne, Switzerland. E-mail: reubi{at}pathology.unibe.ch

Two bombesin analogs, Demobesin 4 and Demobesin 1, were characterized in vitro as gastrin-releasing peptide (GRP) receptor agonist and antagonist, respectively, and were compared as ^99mTc-labeled ligands for their in vitro and in vivo tumor-targeting properties. Methods: N₄-[Pro¹,Tyr⁴,Nle¹⁴]Bombesin (Demobesin 4) and N₄-[D-Phe⁶,Leu-NHEt¹³,des-Met¹⁴]bombesin(6–14) (Demobesin 1) were characterized in vitro for their binding properties with GRP receptor autoradiography using GRP receptor–transfected HEK293 cells, PC3 cells, and human prostate cancer specimens. Their ability to modulate calcium mobilization in PC3 and transfected HEK293 cells was analyzed as well as their ability to trigger internalization of the GRP receptor in transfected HEK293 cells, as determined qualitatively by immunofluorescence microscopy and quantitatively by enzyme-linked immunosorbent assay (ELISA). Further, their internalization properties as ^99mTc-labeled radioligands were tested in vitro in both cell lines. Finally, their biodistribution was analyzed in PC3 tumor–bearing mice. Results: A comparable binding affinity with the 50% inhibitory concentration (IC₅₀) in the nanomolar range was measured for Demobesin 4 and Demobesin 1 in all tested tissues. Demobesin 4 behaved as an agonist by strongly stimulating calcium mobilization and by triggering GRP receptor internalization. Demobesin 1 was ineffective in stimulating calcium mobilization and in triggering GRP receptor internalization. However, in these assays, it behaved as a competitive antagonist as it reversed completely the agonist-induced effects in both systems. ^99mTc-Labeled Demobesin 1 was only weakly taken up by PC3 cells or GRP receptor–transfected HEK293 cells (10% and 5%, respectively, of total added radioactivity) compared with ^99mTc-labeled Demobesin 4 (45% of total added radioactivity in both cell lines). Remarkably, the biodistribution study revealed a much more pronounced uptake at 1, 4, and 24 h after injection of ^99mTc-labeled Demobesin 1 in vivo into PC3 tumors than ^99mTc-labeled Demobesin 4. In vivo competition experiments demonstrated a specific uptake in PC3 tumors and in physiologic GRP receptor–expressing tissues. The tumor-to-kidney ratios were 0.7 for Demobesin 4 and 5.2 for Demobesin 1 at 4 h. Conclusion: This comparative in vitro/in vivo study with Demobesin 1 and Demobesin 4 indicates that GRP receptor antagonists may be superior targeting agents to GRP receptor agonists, suggesting a change of paradigm in the field of bombesin radiopharmaceuticals.

Key Words: tumor targeting • gastrin-releasing peptide receptors • antagonist • bombesin • peptide radiopharmaceuticals

^* Contributed equally to this work.

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.

Related articles in JNM:

This Month in JNM

JNM 2008 49: 11A-12A. [Full Text]  

This article has been cited by other articles:

				R. Mansi, X. Wang, F. Forrer, S. Kneifel, M.-L. Tamma, B. Waser, R. Cescato, J. C. Reubi, and H. R. Maecke Evaluation of a 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid-Conjugated Bombesin-Based Radioantagonist for the Labeling with Single-Photon Emission Computed Tomography, Positron Emission Tomography, and Therapeutic Radionuclides Clin. Cancer Res., August 15, 2009; 15(16): 5240 - 5249. [Abstract] [Full Text] [PDF]

				A. Fleischmann, B. Waser, and J. C. Reubi High expression of gastrin-releasing peptide receptors in the vascular bed of urinary tract cancers: promising candidates for vascular targeting applications Endocr. Relat. Cancer, June 1, 2009; 16(2): 623 - 633. [Abstract] [Full Text] [PDF]

				J. C. Reubi and H. R. Maecke Peptide-Based Probes for Cancer Imaging J. Nucl. Med., November 1, 2008; 49(11): 1735 - 1738. [Abstract] [Full Text] [PDF]