Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes.
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.
Jaquet
P
P
Interactions Cellulaires Neuroendocrines, UMR 6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, Marseille, France. jaquet.p@jean-roche.univ.mrs.fr
Saveanu
A
A
Gunz
G
G
Fina
F
F
Zamora
A J
AJ
Grino
M
M
Culler
M D
MD
Moreau
J P
JP
Enjalbert
A
A
Ouafik
L H
LH
D000172:Acromegaly / Q000378:metabolism*; D000236:Adenoma / Q000378:metabolism; D000328:Adult; D002478:Cells, Cultured; D004338:Drug Combinations; D005260:Female; D006728:Hormones / Q000494:pharmacology; D019382:Human Growth Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D011388:Prolactin / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000819:agonists / Q000235:genetics; D011986:Receptors, Somatotropin / Q000235:genetics*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology
C111784:BIM 23197; C121506:BIM 23268; D004338:Drug Combinations; D006728:Hormones; D009842:Oligopeptides; D010879:Piperazines; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; D011986:Receptors, Somatotropin; C101130:somatostatin receptor type 1; D019382:Human Growth Hormone; D013004:Somatostatin; C094573:somatostatin receptor 5; D011388:Prolactin; C093733:somatostatin receptor 2; D015282:Octreotide