BIM-23244, a somatastatin receptor subtype 2-and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas

Although both somatostatin receptor subtype 2 (SSTR2) and SSTR5 messenger r ibonucleic acid (mRNA) are consistently expressed in GH-secreting adenomas, SSTR2 has been believed to be the key modulator of somatostatin-mediated i nhibition of GH release. The somatostatin agonists currently in clinical us e, octreotide and lanreotide, are directed mainly to SSTR2 (IC50 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 fro m prolactinomas and mixed GH-PBL 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 adenom as. In the present study we quantified SSTR2 and SSTR5 mRNA expression and the GH-suppressive effects of somatostatin-14; octreotide; a SSTR2-preferen tial compound, BIM-23197; a SSTR5-preferential compound, BIM-23268; and a n ew SSTR2- and SSTR5-bispecific compound, BIM-23244, in GH-secreting tumors classified as either full responders to octreotide (n = 5) or partially sen sitive to octreotide (n = 5). The octreotide-sensitive GH secretory adenoma s presented with a high level of both SSTR2 and SSTR5 mRNA expression [222 +/- 61 and 327 +/- 136 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPD H), respectively]. In these tumors the suppression of GH release was simila rly achieved at picomolar ranges by octreotide, BIM-23197, and BIM-23244 (E C50 = 25 +/- 15, 3 +/- 2, and 3 +/- 3 pmol/L, respectively). The compounds preferential for only SSTR5 were unable to inhibit GH release in such tumor s. 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 approxim ately 7-fold higher than in the octreotide-sensitive tumors (2271 +/- 1197 pg/pg GAPDH). In these octreotide partially responsive tumors, the SSTR5-pr eferential compound, BIM-23268, and the SSTR2- and SSTR5-bispecific compoun d, BIM-23244, were quite effective in suppressing GH secretion (EC50 = 25 /- 13 and 50 +/- 31 pmol/L, respectively). Similarly, BIM-23244, was able t o suppress by 51 +/- 5% PRL release from five mixed GH- and PRL-secreting a denomas. These data indicate that due to heterogeneous expression of SSTR2 and SSTR5 receptor subtypes, in GH-secreting tumors, a bispecific analog, s uch as BIM-23244, that can activate both receptors could achieve better con trol of GH hypersecretion in a larger number of acromegalic patients.