BIM-23244, a Somatostatin Receptor Subtype 2- and 5-Selective Analog with Enhanced Efficacy in Suppressing Growth Hormone (GH) from Octreotide-Resistant Human GH-Secreting Adenomas

Abstract

Although both somatostatin receptor subtype 2 (SSTR2) and SSTR5 messenger ribonucleic acid (mRNA) are consistently expressed in GH-secreting adenomas, SSTR2 has been believed to be the key modulator of somatostatin-mediated inhibition of GH release. The somatostatin agonists currently in clinical use, octreotide and lanreotide, are directed mainly to SSTR2 (IC(50) 12- to 18-fold higher than for SSTR5). Recently, however, it was demonstrated that an SSTR5 preferential agonist, BIM-23268, not only suppressed PRL release from prolactinomas and mixed GH-PRL adenomas, but also inhibited GH release in about half of GH adenomas. In addition, the SSTR5-preferring analog showed a slight additive effect when used in combination with SSTR2 preferential drugs at submaximal concentrations in octreotide partially sensitive adenomas. In the present study we quantified SSTR2 and SSTR5 mRNA expression and the GH-suppressive effects of somatostatin-14; octreotide; a SSTR2-preferential compound, BIM-23197; a SSTR5-preferential compound, BIM-23268; and a new SSTR2- and SSTR5-bispecific compound, BIM-23244, in GH-secreting tumors classified as either full responders to octreotide (n = 5) or partially sensitive to octreotide (n = 5). The octreotide-sensitive GH secretory adenomas presented with a high level of both SSTR2 and SSTR5 mRNA expression [222 +/- 61 and 327 +/- 136 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively]. In these tumors the suppression of GH release was similarly achieved at picomolar ranges by octreotide, BIM-23197, and BIM-23244 (EC(50) = 25 +/- 15, 3 +/- 2, and 3 +/- 3 pmol/L, respectively). The compounds preferential for only SSTR5 were unable to inhibit GH release in such tumors. Among the octreotide partially responsive tumors, SSTR2 mRNA expression was 9-fold lower than in the octreotide-sensitive tumors (25 +/- 12 vs. 222 +/- 61 pg/pg GAPDH; P < 0.015), whereas SSTR5 mRNA expression was approximately 7-fold higher than in the octreotide-sensitive tumors (2271 +/- 1197 pg/pg GAPDH). In these octreotide partially responsive tumors, the SSTR5-preferential compound, BIM-23268, and the SSTR2- and SSTR5-bispecific compound, BIM-23244, were quite effective in suppressing GH secretion (EC(50) = 25 +/- 13 and 50 +/- 31 pmol/L, respectively). Similarly, BIM-23244, was able to suppress by 51 +/- 5% PRL release from five mixed GH- and PRL-secreting adenomas. These data indicate that due to heterogeneous expression of SSTR2 and SSTR5 receptor subtypes, in GH-secreting tumors, a bispecific analog, such as BIM-23244, that can activate both receptors could achieve better control of GH hypersecretion in a larger number of acromegalic patients.

A luteinizing hormone-, alpha-subunit- and prolactin-secreting pituitary adenoma responsive to somatostatin analogs: in vivo and in vitro studies

“…Interestingly, the native peptide, SRIF-14, achieved, in our case, significantly higher hormone suppression than that obtained with analogues highly preferential for SSTR5 or SSTR2. These data suggest cooperation between these two receptor subtypes, possibly by heterodimerization, as has been demonstrated using cloned human receptors (23), and already suggested in some GH-secreting pituitary adenomas (24).…”

Function and expression of somatostatin receptors of the endocrine pancreas

“…Agonists A very recent study (Ludvigsen et al, 2007) evaluated the effects of the following agonists on insulin and glucagon secretion from isolated rat pancreatic islets: SOM230 (panagonist), SSTR1-selective (BIM-23926 IC50 of 3.6 nM for SSTR1 and > 800 nM for other SSTRs (Zatelli et al, 2002)), SSTR2-selective (BIM-23120, IC50 of 0.34 nM for SSTR2, and over 200 nM for other SSTRs (Zatelli et al, 2001;Zatelli et al, 2002;Shimon et al, 1997b;Shimon et al, 1997a;Saveanu et al, 2001)) and SSTR5-selective (BIM-23206, IC50 of 2.4 nM for SSTR5 and more than 15 nM for other 4 SSTRs). SOM230 was a superior inhibitor of insulin secretion as compared to octreotide or SST-14 after a longer incubation period of 48 hours.…”

A utilização da octreotida subcutânea ou LAR como teste preditivo e no tratamento da acromegalia

“…Estudos prévios têm sugerido que a supressão do GH num teste agudo com a octreotida poderia refletir in vivoa capacidade de ligação da droga aos receptores da somatostatina, particularmente os subtipos 2 e 5, independentemente da densidade desses receptores nos tumores (20). Entretanto, existem controvérsias na literatura quanto ao valor preditivo deste teste na avaliação da resposta ao tratamento de longo prazo (19,21).…”