This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 John, C. S. Articles by Bowen, W. D. Search for Related Content PubMed PubMed Citation Articles by John, C. S. Articles by Bowen, W. D.

Targeting Sigma Receptor-binding Benzamides as in Vivo Diagnostic and Therapeutic Agents for Human Prostate Tumors¹

Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC 20037 [C. S. J., B. C. G.]; Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, National Institutes of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892 [B. J. V., W. D. B.]; and Cell and Cancer Biology Department, Medicine Branch, National Cancer Institute, Rockville, Maryland 20850 [T. M.]

Sigma receptors are known to be expressed in a variety of human tumor cells, including breast, neural, and melanoma tumors. A very high density (1.0–1.5 million receptors/cell) of sigma receptors was also reported in a human androgen-dependent prostate tumor cell line (LNCaP). In this study, we show that a very high density of sigma receptors is also expressed in an androgen-independent human prostate tumor cell line (DU-145). Pharmacological binding studies using the sigma-1-selective ligand [³H](+)-pentazocine showed a high-affinity binding (K_d = 5.80 nM, B_max = 1800 fmol/mg protein). Similarly, binding studies with [³H]1,3-di-o-tolylguanidine in the presence of dextrallorphan also showed a high-affinity binding (K_d = 15.71 nM, B_max = 1930 fmol/mg protein). Radioiodinated benzamide N-[2-(1'-piperidinyl)ethyl]-3-[¹²⁵I]iodo-4-methoxy-benzamide ([¹²⁵I]PIMBA) was also shown to bind DU-145 cells in a dose-dependent manner. Three different radioiodinated benzamides, [¹²⁵I]PIMBA, 4-[¹²⁵I]iodo-N-[2-(1'-piperidinyl)ethyl]benzamide, and 2-[¹²⁵I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide, were screened for their potential to image human prostate tumors in nude mice bearing human prostate cells (DU-145) xenografts. All three compounds showed a fast clearance from the blood pool and a high uptake and retention in the tumor. Therapeutic potential of nonradioactive PIMBA was studied using in vitro colonogenic assays. A dose-dependent inhibition of cell colony formation was found in two different human prostate cells. These results demonstrate the potential use of sigma receptor binding ligands in noninvasive diagnostic imaging of prostate cancer and its treatment.

This article has been cited by other articles:

				A. Renaudo, S. L'Hoste, H. Guizouarn, F. Borgese, and O. Soriani Cancer Cell Cycle Modulated by a Functional Coupling between Sigma-1 Receptors and Cl- Channels J. Biol. Chem., January 26, 2007; 282(4): 2259 - 2267. [Abstract] [Full Text] [PDF]

				A. Mukherjee, T. K. Prasad, N. M. Rao, and R. Banerjee Haloperidol-associated Stealth Liposomes: A POTENT CARRIER FOR DELIVERING GENES TO HUMAN BREAST CANCER CELLS J. Biol. Chem., April 22, 2005; 280(16): 15619 - 15627. [Abstract] [Full Text] [PDF]

				L. Wang, A. R. Prescott, B. A. Spruce, J. Sanderson, and G. Duncan Sigma Receptor Antagonists Inhibit Human Lens Cell Growth and Induce Pigmentation Invest. Ophthalmol. Vis. Sci., April 1, 2005; 46(4): 1403 - 1408. [Abstract] [Full Text] [PDF]

				A. Renaudo, V. Watry, A.-A. Chassot, G. Ponzio, J. Ehrenfeld, and O. Soriani Inhibition of Tumor Cell Proliferation by {sigma} Ligands Is Associated with K+ Channel Inhibition and p27kip1 Accumulation J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 1105 - 1114. [Abstract] [Full Text] [PDF]

				E. Aydar, C. P. Palmer, and M. B. A. Djamgoz Sigma Receptors and Cancer: Possible Involvement of Ion Channels Cancer Res., August 1, 2004; 64(15): 5029 - 5035. [Abstract] [Full Text] [PDF]

				S. H. Britz-Cunningham and S. J. Adelstein Molecular Targeting with Radionuclides: State of the Science J. Nucl. Med., December 1, 2003; 44(12): 1945 - 1961. [Abstract] [Full Text] [PDF]