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A novel somatostatin conjugate with a high affinity to all five somatostatin receptor subtypes
Ulrich Wulbrand1, Martin Feldman, Andreas Pfestroff
1Clinical Research Unit for Gastrointestinal Endocrinology, Department of Internal Medicine, Philipps-University Marburg, Marburg, Germany.
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.
Insights
A novel somatostatin receptor (SRS) conjugate, SMS-dextran70, demonstrates high affinity for all five SRS subtypes. This conjugate shows potential for treating SRS-positive tumors and is currently under clinical investigation for prostate cancer.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Somatostatin receptors (SRS) are present in various human tumors, including neuroendocrine, breast, brain, renal, lymphoma, and prostate cancers.
- Somatostatin (SMS) exhibits cytostatic and cytotoxic effects, inhibiting secretion via SRS interaction, forming the basis for SRS-positive tumor treatment.
- Radiolabeled SMS analogs are utilized for diagnostic imaging and systemic radiotherapy.
Purpose of the Study:
- To develop and characterize a novel somatostatin receptor-targeting conjugate, SMS-dextran70.
- To evaluate the binding affinity of SMS-dextran70 to all five somatostatin receptor subtypes.
- To assess the therapeutic potential of SMS-dextran70 for SRS-positive tumors.
Main Methods:
- SMS-14 was conjugated to dextran70 via reductive amination.
- Human neuroendocrine tumor cells (LCC-18) were stably transfected with individual SRS genes.
- Binding affinity of the SMS-dextran70 conjugate to each SRS subtype was determined.
Main Results:
- SMS-dextran70 exhibited high-affinity binding across all five somatostatin receptor subtypes.
- The IC50 values for SMS-dextran70 ranged from 3 to 80 nM.
- The conjugate demonstrated a long circulation half-life of approximately 27 hours in mice after subcutaneous administration.
Conclusions:
- SMS-dextran70 possesses high pan-affinity for somatostatin receptors and a favorable pharmacokinetic profile.
- The conjugate holds significant potential for the therapy of SRS-positive tumors.
- A Phase I-II clinical trial is ongoing to evaluate SMS-dextran70 in patients with hormone-refractory prostate cancer.