title: Somatostatin receptor-specific analogs: effects on cell proliferation and growth hormone secretion in human somatotroph tumors.
abstract: Somatostatin (SST) acts through a family of seven transmembrane domain G protein-coupled receptors to inhibit hormone secretion and cell proliferation in a variety of neuroendocrine tissues. In normal and neoplastic human pituitary somatotroph cells, SST-specific receptor types (SSTR) 1, 2, 3, and 5 are prevalently expressed, and SST and its analogs have been shown to inhibit GH secretion. However, in somatotroph adenomas, little is known regarding: 1) effects of SST and its analogs on pituitary tumor proliferation; 2) the relationship between the effects of SST analogs on GH secretion and tumor cell proliferation; and 3) whether SSTR expression predicts the antiproliferative effects of SST analogs in human somatotroph tumors. We investigated the effects of SST-14, lanreotide, and SSTR 2 (BIM-23190) and SSTR 5 (BIM-23268) specific analogs in 18 somatotroph pituitary adenomas in primary culture. Our results showed that cell proliferation was significantly inhibited by SST-14, lanreotide, BIM-23190, and BIM-23268 in 4, 7, 3, and 4 tumors, respectively (range of proliferation suppression 5-60%; median, 16%). Tumors that were responsive to SSTR 2- and 5-specific analogs were also responsive to lanreotide. SST-14 inhibited GH secretion in 8 of 13 tumors; lanreotide, BIM-23190, and BIM-23268 inhibited GH secretion in six tumors each (range of GH secretion inhibition 23-43%; median 33%). SSTR 2 and 5 messenger RNA was expressed in all tumors investigated, whereas SSTR 1 and 3 messenger RNA was expressed in 11 and 12 tumors, respectively. We observed a dissociation between the in vitro effects of SST-14 or lanreotide on tumor cell proliferation and the effects on GH secretion in human somatotroph tumors. Although differences in receptor concentration and the presence of other SST receptor subtypes may play a role, the presence of SSTR 2 and/or 5 did not have a predictive value. These data suggest that inhibition of cell proliferation occurs independently of effects on GH secretory pathways. Further studies are needed to clarify the mechanism of SST induced antiproliferative effects.
authors.affiliation: Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston Massachusetts 02114, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Danila
authors.forename: J N
authors.initials: JN
authors.lastname: Haidar
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Katznelson
authors.forename: M D
authors.initials: MD
authors.lastname: Culler
authors.forename: A
authors.initials: A
authors.lastname: Klibanski
mesh_terms: D000172:Acromegaly; D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D002455:Cell Division / Q000187:drug effects*; D005260:Female; D015870:Gene Expression; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000494:pharmacology; D010911:Pituitary Neoplasms / Q000378:metabolism / Q000473:pathology*; D011388:Prolactin / Q000097:blood; D012333:RNA, Messenger / Q000032:analysis; D017481:Receptors, Somatostatin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D010456:Peptides, Cyclic; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C060347:lanreotide; D019382:Human Growth Hormone; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D011388:Prolactin