A novel somatostatin conjugate with a high affinity to all five somatostatin receptor subtypes

BACKGROUND Somatostatin receptors (SRS, five subtypes) are expressed in a variety of human tumors, including most tumors of neuroendocrine origin, breast tumors, certain brain tumors, renal cell tumors, lymphomas, and prostate cancer. Somatostatin (SMS) triggers cytostatic and cytotoxic effects and...

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Published in:	Cancer Vol. 94; no. S4; pp. 1293 - 1297
Main Authors:	Wulbrand, Ulrich, Feldman, Martin, Pfestroff, Andreas, Fehman, Hans‐Cristophe, Du, Jin, Hiltunen, Jukka, Marquez, Marcela, Arnold, Rudolf, Westlin, Jan‐Erik, Nilsson, Sten, Holmberg, Anders R.
Format:	Journal Article Conference Proceeding
Language:	English
Published:	New York John Wiley & Sons, Inc 15-02-2002 Wiley-Liss
Subjects:	Antineoplastic agents Biological and medical sciences Dextrans - chemistry Dextrans - pharmacokinetics Drug Delivery Systems - methods General aspects Glycosylation Half-Life Humans Medical sciences Medicin och hälsovetenskap octreotide pan‐affinity Pharmacology. Drug treatments receptor subtypes Receptors, Somatostatin - drug effects Receptors, Somatostatin - genetics Receptors, Somatostatin - metabolism Somatostatin - chemistry Somatostatin - metabolism somatostatin‐14 somatostatin‐dextran70 Transfection Tumor Cells, Cultured Antineoplastic agent Dextran Binding capacity Peptide hormone Conjugation Somatostatin Neuropeptide Subtype Biological receptor Hormonal receptor
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Summary:	BACKGROUND Somatostatin receptors (SRS, five subtypes) are expressed in a variety of human tumors, including most tumors of neuroendocrine origin, breast tumors, certain brain tumors, renal cell tumors, lymphomas, and prostate cancer. Somatostatin (SMS) triggers cytostatic and cytotoxic effects and has a general inhibitory effect on secretion mediated through its interaction with SRS. That is the basis for its use in the treatment of SRS‐positive tumors. Radiolabeled SMS analogs can also be used for systemic radiotherapy and for diagnostic investigations. METHODS Sms‐14 was conjugated to a periodate‐activated dextran70 (mean molecular weight, 70 kD) by reductive amination. The human tumor cell line LCC‐18, from a neuroendocrine colonic tumor, was used for stable transfection with each SRS gene separately; transfection was achieved with the expression system TETon (Clontech, Palo Alto, CA). Clones were selected by culturing with G418 and hygromycin B, and positive clones were identified by reverse transcriptase–polymerase chain reaction and binding of iodine‐125–labeled SMS‐14. The binding affinity for each SRS subtype was then determined for the SMS‐dextran conjugate (with SMS‐14 used as a positive control). RESULTS Sms‐dextran70 showed high affinity binding to all five receptor subtypes. The IC50 values were between 3 and 80 nM. CONCLUSIONS This conjugate has a long circulation half‐life (i.e., ≈27 hours after subcutaneous administration in mice) and, with high SRS pan‐affinity demonstrated in this study, it has potential in the therapy of SRS‐positive tumors. Currently, the clinical significance of SMS‐dextran70 is being explored in a clinical Phase I–II study of patients with hormone‐refractory prostate cancer. The outcome of this study will be reported when it is available. Cancer 2002;94:1293–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10299 Somatostatin‐dextran70 has a high affinity to all five somatostatin receptor subtypes.
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ISSN:	0008-543X 1097-0142
DOI:	10.1002/cncr.10299