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

Abstract

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

Characterisation of biomolecular profiles in primary high-grade prostate cancer treated by radical prostatectomy

“…In future, new therapeutic approaches (i.e., somatostatin) for prostate cancers with neuroendocrine differentiation might be a possible alternative. So far, they are currently under intensive investigation (Wulbrand et al 2002).…”

Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms

“…carcinoid syndrome, Verner-Morrison syndrome) or in inhibiting tumour progression in patients with advanced disease. The anti-tumour effect of SSAs may include both a cytostatic (growth arrest) and a cytotoxic (pro-apoptosis) mechanism (Balaban & Severs 1992, Bousquet et al 2001, Wulbrand et al 2002, Ferrante et al 2006, Pyronnet et al 2008. However, there is still little known regarding the antiproliferative role of SSA in NETs, although increasing data suggest that such analogues can be tumouristatic, at least in some circumstances (Jensen 2000).…”

Nanocarriers for Nuclear Imaging and Radiotherapy of Cancer

“…Following conjugation with dextran to improve its in vivo kinetics [196], biodistribution 99m Tc or 125 I labeled dextran-somatostatin revealed good in vivo stability of the conjugate, increased plasma half and high affinity accumulation in tumors [196,206,207]. Phase I trials of 131 I labeled dextran-somatostatin conjugate injected subcutaneously once a week in patients with metastatic prostate or renal cancer showed long blood half-life and no cases of drug induced toxicity [208].…”