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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 Adenomas¹

Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche 6544, Centre National de la Recherche Scientifique (A.S., G.G., A.E., P.J.), and Laboratoire de Transfert d’Oncologie Biologique-Assistance Publique-Hôpitaux de Marseilles (L.O., F.F.), Institut Fédératif Jean Roche, Faculté de Médecine Nord, 13916 Marseilles, France; Service de Neurochirurgie, Centre Hospitalier de Marseilles, Hôpital de la Timone (H.D.), 13005 Marseilles, France; Service d’Endocrinologie de Toulouse (P.C.), 31403 Toulouse, France; and Biomeasure, Inc. (M.D.C., J.P.M.), Milford, Massachusetts 01757

Address all correspondence and requests for reprints to: Dr. Philippe Jaquet, Interactions Cellulaires Neuroendocriniennes-Unité Mixte de Recherche 6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, boulevard Pierre Dramard, 13916 Marseilles Cedex 20, France.

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 (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 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 (EC₅₀ = 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 (EC₅₀ = 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.

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