title: Targeting sigma receptor-binding benzamides as in vivo diagnostic and therapeutic agents for human prostate tumors.
abstract: 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 (Kd = 5.80 nM, Bmax = 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 (Kd = 15.71 nM, Bmax = 1930 fmol/mg protein). Radioiodinated benzamide N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide ([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 non-invasive diagnostic imaging of prostate cancer and its treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC 20037, USA. radcsj@gwumc.edu
authors.forename: C S
authors.initials: CS
authors.lastname: John
authors.forename: B J
authors.initials: BJ
authors.lastname: Vilner
authors.forename: B C
authors.initials: BC
authors.lastname: Geyer
authors.forename: T
authors.initials: T
authors.lastname: Moody
authors.forename: W D
authors.initials: WD
authors.lastname: Bowen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007977:Levallorphan / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010423:Pentazocine / Q000493:pharmacokinetics; D010880:Piperidines / Q000493:pharmacokinetics*; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy; D051381:Rats; D017480:Receptors, sigma / Q000032:analysis* / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007457:Iodine Radioisotopes; C120391:N-(2-(1'-piperidinyl)ethyl)-3-iodo-4-methoxybenzamide; D010880:Piperidines; D017480:Receptors, sigma; D007977:Levallorphan; C044130:dextrallorphan; D010423:Pentazocine