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 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., approximately 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.
Wulbrand
Ulrich
U
Clinical Research Unit for Gastrointestinal Endocrinology, Department of Internal Medicine, Philipps-University Marburg, Marburg, Germany.
Feldman
Martin
M
Pfestroff
Andreas
A
Fehman
Hans-Cristophe
HC
Du
Jin
J
Hiltunen
Jukka
J
Marquez
Marcela
M
Arnold
Rudolf
R
Westlin
Jan-Erik
JE
Nilsson
Sten
S
Holmberg
Anders R
AR
D003911:Dextrans / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D006031:Glycosylation; D006207:Half-Life; D006801:Humans; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013004:Somatostatin / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D003911:Dextrans; D017481:Receptors, Somatostatin; D013004:Somatostatin