title: 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., 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.
authors.affiliation: Clinical Research Unit for Gastrointestinal Endocrinology, Department of Internal Medicine, Philipps-University Marburg, Marburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wulbrand
authors.forename: Martin
authors.initials: M
authors.lastname: Feldman
authors.forename: Andreas
authors.initials: A
authors.lastname: Pfestroff
authors.forename: Hans-Cristophe
authors.initials: HC
authors.lastname: Fehman
authors.forename: Jin
authors.initials: J
authors.lastname: Du
authors.forename: Jukka
authors.initials: J
authors.lastname: Hiltunen
authors.forename: Marcela
authors.initials: M
authors.lastname: Marquez
authors.forename: Rudolf
authors.initials: R
authors.lastname: Arnold
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Westlin
authors.forename: Sten
authors.initials: S
authors.lastname: Nilsson
authors.forename: Anders R
authors.initials: AR
authors.lastname: Holmberg
mesh_terms: 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
chemical_list: D003911:Dextrans; D017481:Receptors, Somatostatin; D013004:Somatostatin