Somatostatin receptor-specific analogs: Effects on cell proliferation and growth hormone secretion in human somatotroph tumors

Somatostatin (ST) acts through a family of seven transmembrane domain G pro tein-coupled receptors to: inhibit hormone secretion and cell proliferation in a variety of neuroendocrine tissues. In normal and neoplastic human pit uitary somatotroph cells, SST-specific receptor types (SSTR) 1, 2, 3, and 5 are prevalently expressed, and SST and its analogs have been shown to inhi bit GH secretion. However, in somatotroph adenomas, little is known regardi ng: 1) effects of SST and its analogs on pituitary tumor proliferation; 2) the relationship between the effects of SST analogs on GH secretion and tum or cell proliferation; and 3) whether SSTR expression predicts the antiprol iferative effects of SST analogs in human somatotroph tumors. We investigated the effects of SST-14,;lanreotide, and SSTR 2 (BIM-23190) a nd SSTR 5 (BIM-23268) specific analogs in 18 somatotroph pituitary adenomas in primary culture. Our results showed that cell proliferation was signifi cantly inhibited by SST-14, lanreotide, BIM-23190, and BIM-23268 in 4, 7, 3 , and 4 tumors, respectively (range of proliferation suppression 5-60%; med ian, 16%). Tumors that were responsive to SSTR 2- and 5-specific analogs me re also responsive to lanreotide. SST-14 inhibited GH. secretion in 8 of 13 tumors; lanreotide, BIM-231901 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 II and 12 tumors, respectively. We o bserved a dissociation between the in vitro effects of SST-14 or lanreotide on tumor cell proliferation and the effects on GK secretion in human somat otroph tumors. Although differences in receptor concentration and the prese nce of other SST receptor subtypes may play a role, the presence of SSTR 2 and/of 5 did. not have a predictive value. These data suggest that inhibiti on of cell proliferation occurs independently of effects on GH secretory pa thways. Further studies are needed to clarify the mechanism of SST induced antiproliferative effects.