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Titolo:
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
Autore:
Saveanu, A; Gunz, G; Dufour, H; Caron, P; Fina, F; Ouafik, L; Culler, MD; Moreau, JP; Enjalbert, A; Jaquet, P;
Indirizzi:
Fac Med Nord, Inst Federat Jean Roche, CNRS, Unite Mixte Rech 6544, F-13916 Marseille, France Fac Med Nord Marseille France F-13916 ch 6544, F-13916 Marseille, France Assistance Publ Hop Marseilles, Fac Med Nord, Inst Federat Jean Roche, LabTransfert Oncol Biol, F-13916 Marseille, France Assistance Publ Hop Marseilles Marseille France F-13916 arseille, France Ctr Hosp Marseille, Hop Timone, Serv Neurochirurg, F-13005 Marseille, France Ctr Hosp Marseille Marseille France F-13005 g, F-13005 Marseille, France Serv Endocrinol Toulouse, F-31403 Toulouse, France Serv Endocrinol Toulouse Toulouse France F-31403 -31403 Toulouse, France Biomeasure Inc, Milford, MA 01757 USA Biomeasure Inc Milford MA USA 01757Biomeasure Inc, Milford, MA 01757 USA
Titolo Testata:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
fascicolo: 1, volume: 86, anno: 2001,
pagine: 140 - 145
SICI:
0021-972X(200101)86:1<140:BASRS2>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN PITUITARY-ADENOMAS; SOMATOSTATIN RECEPTORS; ACROMEGALIC PATIENTS; MESSENGER-RNA; SLOW-RELEASE; EXPRESSION; TUMORS; TRANSCRIPTION; MULTICENTER; LANREOTIDE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
29
Recensione:
Indirizzi per estratti:
Indirizzo: Jaquet, P Fac Med Nord, Inst Federat Jean Roche, CNRS, Interact Cellulaires Neuroendocriniennes Unite Mi, Blvd Pierre Dramard, F-13916 Marseille 20, France Fac Med Nord Blvd Pierre Dramard Marseille France 20 20, France
Citazione:
A. Saveanu et al., "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", J CLIN END, 86(1), 2001, pp. 140-145

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 (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-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 preferentialdrugs at submaximal concentrations in octreotide partially sensitive adenomas. In the present study we quantified SSTR2 and SSTR5 mRNA expression andthe 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 tumorsclassified 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 compoundspreferential for only SSTR5 were unable to inhibit GH release in such tumors. Among the octreotide partially responsive tumors, SSTR2 mRNA expressionwas 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 +/- 1197pg/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 SSTR2and 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/12/20 alle ore 18:20:02