DISSOCIATION BETWEEN THE EFFECTS OF SOMATOSTATIN (SS) AND OCTAPEPTIDESS-ANALOGS ON HORMONE-RELEASE IN A SMALL SUBGROUP OF PITUITARY-TUMOR AND ISLET-CELL-TUMOR

The effects of somatostatin (SS-14 and/or SS-28) and of the three octa peptide SS-analogs that are available for clinical use (octreotide, BI M-23014 and RC-160) on hormone release by primary cultures of 15 clini cally nonfunctioning pituitary adenomas (NFA), 7 prolactinomas, and 2 insulinomas were investigated. In the pituitary adenoma cultures, a co mparison was made with the effects of the dopamine (DA) agonists bromo criptine and/or quinagolide. In 5 NFAs, 2 prolactinomas and 1 insulino ma somatostatin receptor (subtype) expression was determined by ligand binding studies and by in situ hybridization to detect sst(1), sst(2) , and sst(3) messenger RNAs (mRNAs). Four NFA cultures did not secrete detectable amounts of alpha-subunit, FSH, and/or LH. In the other cul tures, hormone and/or subunit release was inhibited by DA-agonists (10 nM) in 9 of 11, by SS (10 nM) in 7 of 11, and by octapeptide SS-analo gs (10 nM) in 3 of 10 cultures. In three NFA cultures, hormone release was sensitive to SS but not to SS-analogs. In all cultures, except fo r one, DA-agonists were the most effective in inhibiting hormone relea se. In the prolactinoma cultures, PRL release was inhibited by DA-agon ists (10 nM) in 7 of 7, by SS in 4 of 4, and by octapeptide SS-analogs in 3 of 7 cultures. A dissociation between the effects of SS and SS-a nalogs was found in 3 cases. In the cultures sensitive to both bromocr iptine and SS-28, bromocriptine was the most potent compound in 2 out of 4 cultures. In the 2 other cultures, both compounds were equally ef fective. In 2 insulinoma cultures, insulin release was inhibited by SS , and by octapeptide SS-analogs in only one. The presence or absence o f an inhibitory effect by octreotide was in all cases in parallel with the presence or absence of the inhibitory effect by BIM-23014 and RC- 160. Autoradiographic studies using [I-125-Tyr(0)]SS28 showed specific binding in 4 of 5 NFAs, 1 of 2 prolactinomas, and 1 of 1 insulinoma. Specific [I-125-Tyr(3)]octreotide binding was found in 2 of 5 NFAs, in 1 of 2 prolactinomas,and in the insulinoma. Two NFAs showed binding o f SS28, but not of the sst(2,5) specific ligand octreotide. The tumors showed variable sst(1) and/or sst(3) mRNA expression, whereas no sst( 2) expression was found. In conclusion, a dissociation between the inh ibitory effects of SS on the one hand and of the octapeptide SS-analog s octreotide, BIM-23014 and RC-160 on the other hand, is observed in a small subgroup of NFAs, prolactinomas, and insulinomas, suggesting th at novel sst subtype specific SS-analogs might be of benefit in the tr eatment of selected patients with somatostatin receptor positive secre ting tumors not responding to octapeptide SS-analogs. However, in the majority of NFAs and prolactinomas, DA-agonists were equally or more e ffective than SS in the suppression of tumoral secretion products.