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Human Somatostatin Receptor Subtypes in Acromegaly: Distinct Patterns of Messenger Ribonucleic Acid Expression and Hormone Suppression Identify Different Tumoral Phenotypes¹

Interactions Cellulaires Neuroendocrines, UMR 6544, Centre National de la Recherche Scientifique (P.J., A.S., G.G., A.J.Z., A.E.); Laboratoire de Transfert d’Oncologie Biologique-Assistance Publique Hopitaux de Marseille (F.F., L’H.O.); and Unit 501, INSERM (M.G.), Institut Fédératif Jean Roche, Faculté de Médecine Nord, 13916 Marseille Cedex 20, France; and Biomeasure, Inc. (M.D.C., J.P.M.), Milford, Massachussetts 01757

Address all correspondence and requests for reprints to: Dr. Philippe Jaquet, Interactions Cellulaires Neuroendocrines, UMR 6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, boulevard Pierre Dramard, 13916 Marseille Cedex 20, France. E-mail: jaquet.p{at}jean-roche.univ.mrs.fr

Recently, studies using somatostatin (SRIF) analogs preferential for either the SRIF receptor 2 (SSTR2) or the SSTR5 subtype demonstrated a variable suppression of GH and PRL release from GH-secreting human adenomas. These data suggested the concept of SSTR subtype specificity in such tumors. In the present study the quantitative expression of messenger ribonucleic acid (mRNA) for the 5 SSTR subtypes and the inhibitory effects of SRIF14; SRIF28; octreotide; the SSTR2-preferential analog, BIM-23197; and the SSTR5-preferential analog, BIM-23268, on GH and PRL secretion were analyzed in cells cultured from 15 acromegalic tumors. RT-PCR analysis revealed a consistent pattern of SSTR2 and SSTR5 mRNA expression. SSTR5 mRNA was expressed at a higher level (1052 ± 405 pg/pg glyceraldehyde-3-phosphate dehydrogenase) than SSTR2 mRNA (100 ± 30 pg/pg glyceraldehyde-3-phosphate dehydrogenase). However, only SSTR2 mRNA expression correlated with the degree of GH inhibition induced by SRIF14, SRIF28, and BIM-23197. The SSTR5-preferential compound inhibited GH release in only 7 of 15 cases.

In cells cultured from the 10 mixed adenomas that secreted both GH and PRL, RT-PCR analysis revealed a consistent coexpression of SSTR5, SSTR2, and SSTR1 mRNA. In all cases SRIF14, SRIF28, and the SSTR5-preferential analog, BIM-23268, significantly suppressed PRL secretion, with a mean maximal inhibition of 48 ± 4%. In contrast, the SSTR2-preferential analogs, BIM-23197 and octreotide, were effective in suppressing PRL in only 6 of 10 cases. In cells cultured from adenomas taken from patients partially responsive to the SRIF analog, octreotide, partial additivity in suppressing both GH and PRL secretion was observed when the SSTR2- and SSTR5-preferring analogs, BIM-23197 and BIM-23268, were tested in combination. Our data show a highly variable ratio of the SSTR2 and SSTR5 transcripts, according to tumors. The SSTR2-preferring compound consistently inhibits GH release, whereas the SSTR5-preferring compound is the main inhibitor of PRL secretion. When both drugs are combined, the partial additivity observed in mixed GH- plus PRL-secreting adenomas may be of interest in the therapeutic approach of such tumors.

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