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The Novel Somatostatin Analog SOM230 Is a Potent Inhibitor of Hormone Release by Growth Hormone- and Prolactin-Secreting Pituitary Adenomas in Vitro

Department of Internal Medicine (L.J.H., J.v.d..H., P.M.v.K., W.W.d.H., M.W., D.S.-M., R.F., A.-J.v.d.L., S.W.J.L.), Section of Endocrinology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; Research Transplantation (C.B., G.W.), Novartis Pharma A.G., Basel, Switzerland CH-4002; Service d’Endocrinologie (A.B.), Center Hospitalier Universitaire de Liege, Domaine Universitaire du Sart-Tilman, Liege, Belgium 4000

Address all correspondence and requests for reprints to: Leo J. Hofland, Ph.D., Department of Internal Medicine, Section of Endocrinology, Room EE585, Erasmus MC, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: l.hofland{at}erasmusmc.nl.

To determine the inhibitory profile of the novel somatostatin (SRIF) analog SOM230 with broad SRIF receptor binding, we compared the in vitro effects of SOM230, octreotide (OCT), and SRIF-14 on hormone release by cultures of different types of secreting pituitary adenomas. OCT (10 nM) significantly inhibited GH release in seven of nine GH-secreting pituitary adenoma cultures (range, –26 to –73%), SOM230 (10 nM) in eight of nine cultures (range, –22 to –68%), and SRIF-14 (10 nM) in six of six cultures (range, –30 to –75%). The sst analysis showed predominant but variable levels of somatostatin receptor (sst)₂ and sst₅ mRNA expression. In one culture completely resistant to OCT, SOM230 and SRIF-14 significantly inhibited GH release in a dose-dependent manner with an IC₅₀ value in the low nanomolar range. In the other cultures, SOM230 showed a lower potency of GH release inhibition (IC₅₀, 0.5 nM), compared with OCT (IC₅₀, 0.02 nM) and SRIF-14 (IC₅₀, 0.02 nM). A positive correlation was found between sst₂ but not sst₅ mRNA levels in the adenoma cells and the inhibitory potency of OCT on GH release in vivo and in vitro, and the effects of SOM230 and SRIF-14 in vitro. In three prolactinoma cultures, 10 nM OCT weakly inhibited prolactin (PRL) release in only one (–28%), whereas 10 nM SOM230 significantly inhibited PRL release in three of three cultures (–23, –51, and –64.0%). The inhibition of PRL release by SOM230 was related to the expression level of sst₅ but not sst₂ mRNA. Several conclusions were reached. First, SOM230 has a broad profile of inhibition of tumoral pituitary hormone release in the low nanomolar range, probably mediated via both sst₂ and sst₅ receptors. The higher number of responders of GH-secreting pituitary adenoma cultures to SOM230, compared with OCT, suggest that SOM230 has the potency to increase the number of acromegalic patients which can be biochemically controlled. Second, compared with OCT, SOM230 is more potent in inhibiting PRL release by mixed GH/PRL-secreting adenoma and prolactinoma cells.

Abbreviations: DA, Dopamine; hprt, hypoxanthine-phosphoribosyl-transferase; OCT, octreotide; PRL, prolactin; SRIF, somatostatin; sst, somatostatin receptor.

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