Somatostatin analogs for diagnosis and treatment of cancer
Abstract
Somatostatin (SRIF) is a cyclic tetradecapeptide hormone initially isolated from ovine hypothalami. It inhibits endocrine and exocrine secretion, as well as tumor cell growth, by binding to specific cell surface receptors. Its potent inhibitory activity, however, is limited by its rapid enzymatic degradation and the consequent short plasma half-life.
Octreotide is a short SRIF analog with increased duration of action compared to SRIF. Octreotide is approved for the treatment of acromegaly, amine precursor uptake and decarboxylation-omas, complications of pancreatic surgery and severe forms of diarrhea.
Preclinical studies have focussed on the anticancer effects of octreotide and the related SRIF analogs BIM 23014 and RC-160. In vitro at nanomolar concentrations, these analogs inhibit the growth of tumor cells that express high affinity SRIF receptors. Accordingly, SRIF analogs, such as octreotide, potently inhibit the growth of SRIF receptor-positive tumors in various rodent models, and, in particular, xenotransplanted human tumors in nude mice.
The range of cancers susceptible to octreotide and related SRIF analogs includes mammary, pancreatic, colorectal and lung malignancies. Moreover, an indirect antiproliferative effect of SRIF analogs is achievable in SRIF receptor-negative tumors, whose growth is driven by factors (gastrin, insulin-like growth factor-1, etc.) that are downregulated by SRIF.
The use of radiolabeled somatostatin analogs represents a new diagnostic approach. [111In-DTPA]octreotide was developed for gamma camera imaging of SRIF receptor-positive malignancies, such as gasteroenteropancreatic tumors. Visualization of SRIF receptor-positive tumors in humans is emerging as an important methodology, both in tumor staging and predicting therapeutic response to octreotide.
Recently, five SRIF receptor subtypes (SSTR1-5) have been cloned, all of which bind SRIF with high affinity. In contrast, SRIF receptor subtypes 1-5 have different binding profiles for short SRIF analogs. Octreotide, SSTR5, show moderate affinity for SSTR3 and fail to bind with high affinity to the other subtypes (SSTR1 and 4). Accordingly, the oncological profile of these three analogs is apparently similar.
In conclusion, somatostatin analogs are a promising class of compounds for diagnosis and treatment of cancer. Current work is focussed on the identification of further SRIF receptor subtype-selective analogs with potential in oncology.
See also:
- Official Web Site: The Di Bella Method;
- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;
- Publication: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);
- Publication: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);
- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);
- Neuroblastoma: Complete objective response to biological treatment;
- Large B-cells Non-Hodgkin's Lymphoma, Stage IV-AE: a Case Report;
- Non-Hodgkin's Lymphoma, Stage III-B-E: a Case Report;
- Oesophageal squamocellular carcinoma: a complete and objective response;
- Pancreatic Adenocarcinoma: clinical records on 17 patients treated with Di Bella's Method;
- Complete objective response to biological therapy of plurifocal breast carcinoma.