SOMATOSTATIN ANALOGS FOR DIAGNOSIS AND TREATMENT OF CANCER

Somatostatin (SRIF) is a cyclic tetradecapeptide hormone initially iso lated from ovine hypothalami. It inhibits endocrine and exocrine secre tion, as well as tumor cell growth, by binding to specific cell surfac e receptors. Its potent inhibitory activity, however, is limited by it s rapid enzymatic degradation and the consequent short plasma half-lif e. Octreotide is a short SRIF analog with increased duration of action compared to SRIF. Octreotide is approved for the treatment of acromeg aly, 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 concentration s, these analogs inhibit the growth of tumor cells that express high a ffinity SRIF receptors. Accordingly, SRIF analogs, such as octreotide, potently inhibit the growth of SRIF receptor-positive tumors in vario us 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 malign ancies. Moreover, an indirect antiproliferative effect of SRIF analogs is achievable in SRIF receptor-negative tumors, whose growth is drive n by factors (gastrin, insulin-like growth factor-1, etc.) that are do wnregulated by SRIF. The use of radiolabeled somatostatin analogs repr esents a new diagnostic approach. [In-111-DTPA]octreotide was develope d for gamma camera imaging of SRIF receptor-positive malignancies, suc h as gasteroenteropancreatic tumors. Visualization of SRIF receptor-po sitive tumors in humans is emerging as an important methodology, both in tumor staging and predicting therapeutic response to octreotide. Re cently, five SRIF receptor subtypes (SSTR1-5) have been cloned, all of which bind SRIF with high affinity. In contrast, SRIF receptor subtyp es 1-5 have different binding profiles for short SRIF analogs. Octreot ide, RC-160 and BIM 23014 are very similar in that they bind with high affinity to SSTR2 and SSTR5, show moderate affinity for SSTR3 and fai l to bind with high affinity to the other subtypes (SSTR1 and 4). Acco rdingly, 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 focus sed on the identification of further SRIF receptor subtype-selective a nalogs with potential in oncology.