Development of various somatostatin analogs for the treatment and diagnosis of tumors utilizing somatostatin receptor genes

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Somatostatin exerts its effect through its specific high affinity receptors. We have previously reported cloning, functional characterization, and tissue distribution of two subtypes of human and mouse somatostatin receptors (SSTR1, SSTR2). In the present study, we have cloned three additional human somatostatin receptors (SSTR1, SSTR2, SSTR3). Human SSTR1, SSTR2, and SSTR3 are proteins of 418, 388, and 364 amino acids, respectively, RNA blotting studies have revealed that SSTR3 mRNA was detected in human brain and SSTR4 mRNA was present in human pancreatic cancer cell line, MIA PaCa2, while SSTR5 mRNA was not detected in the human tissues examined. The SSTR3 mRNA was expressed at high levels in rat pancreatic islets as well. The human SSTR3, SSTR4, and SSTR5 exhibit specfic binding to somatostatin-14 with IC50 values 1.7, 1.6 and 0.16nM, respectively. We also have characterized the binding affinity of various somatostatin analogs to the SSTR3, 4, and 5. The rank of the potency of the analogs are : somatostatin 28 (SS-28) = CGP 23996>somatostatin-14 (SS-14)>SMS201-995 for hSSTR3 ; SS-14=SS-28>>RC-160>>SMS201-995 for hSSTR4 and SS-28>SS-14>>RC-160>SMS201-995 for hSSTR5. We have determined somatostatin receptor subtypes expressed human endocrine tumors. In two cases of glucagonomas, all the SSTR subtype mRNAs except for SSTR5 mRNA were expressed. In 4 cases of insulinoma, there was a heterogeneous expression hSSTRs. In a carcinoid, SSTR1 and SSTR4 mRNA were detected. Since somatostatin analog, SMS201-995 which has been approved for the treatment of endocrine tumors, was effective in the treatment of a patient with glucagonoma in which SSTR2 mRNA was present, whereas it had no effect in a patient with carcinoid in which SSTR2 mRNA was not detected, these results suggest that the efficacy of SMS201-995 may depend, at least in part, on the expression of SSTR2 in tumors. Cloning of five human somatostatin receptor subtypes facilitates the development of various somatosta