Targeting Sigma Receptor-Binding Benzamides As in Vivo Diagnostic and Therapeutic Agents for Human Prostate Tumors1
[CANCER RESEARCH 59, 4578–4583, September 15, 1999] Targeting Sigma Receptor-binding Benzamides as in Vivo Diagnostic and Therapeutic Agents for Human Prostate Tumors1 Christy S. John,2 Bertold J. Vilner, Brian C. Geyer, Terry Moody, and Wayne D. Bowen 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.] ABSTRACT currently limited by routine diagnostic modalities, such as magnetic resonance imaging, computed tomography, and ultrasound. The skel- Sigma receptors are known to be expressed in a variety of human etal metastases are routinely diagnosed with radionuclide skeletal tumor cells, including breast, neural, and melanoma tumors. A very high imaging. However, the soft tissue metastases and involvement of density (1.0–1.5 million receptors/cell) of sigma receptors was also re- ported in a human androgen-dependent prostate tumor cell line (LNCaP). pelvic lymph nodes cannot be accurately assessed with current tech- In this study, we show that a very high density of sigma receptors is also niques. Therefore, there is a need for a reliable noninvasive diagnostic expressed in an androgen-independent human prostate tumor cell line procedure to determine the lymphatic and soft tissue spread of pros- (DU-145). Pharmacological binding studies using the sigma-1-selective tate neoplasm. Accurate, early detection of prostate tumor and its 3 1 5 ligand [ H]( )-pentazocine showed a high-affinity binding (Kd 5.80 nM, metastases would improve patient management and outcome of ther- 5 3 111 Bmax 1800 fmol/mg protein).
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