Journal of Neuroendocrinolog~, 1995, l41. zyxwvutsrqpon 7, 645-651 zyxwvuts Effects of Chronic Octreotide Treatment on GH Secretory Dynamics and Tumor Growth in Rats Bearing an Ectopic Somatotroph (GC) Tumor Franqoise Mounier, Marie Therese Bluet-Pajot, Cecile Viollet, J e r h e Bertherat, Jose Timsit*, Gloria S. Tannenbaumt and Jacques Epelbaum U.159 INSERM, 2 ter rue d'Alesia, 75014, zyxwvuts *U.24 INSERM, 149 rue de Sevres, 75015, Paris, France. ?Departments of Pediatrics and Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. Key words: somatostatin receptor subtypes, GC pituitary cells, GH, IGFl, insulin Abstract The effects of octreotide, a long-acting somatostatin agonist selective of the sstr2/sstr3/sstr5 receptor subtypes, on ectopic GH secretion and tumor growth were investigated in Wistar-Furth female rats implanted with GH secreting (GC) cells which express mostly somatostatin receptors of the sstrl and sstr2 subtypes. Octreotide dose dependently inhibited thymidine incorporation (- 57%) and GH secretion (-41 zyxwvutsrqpo YO) from GC cells in culture. zyxwvutsrqp In vivo, 6 weeks after GC cell implantation, plasma GH, IGF-1 and insulin levels were highly elevated. Cluster analysis of GH secretory dynamics revealed that GH secretion was less pulsatile in GC-implanted than in control animals. Furthermore, in GC-implanted animals, passive immunization either with SRIH or GHRH antisera did not affect GH plasma levels. Three weeks after GC cell implantation, when tumors became palpable, octreotide (1 yg/h/kg BW) or saline was infused constantly for three weeks by osmotic minipumps. In octreotide treated rats, GH, IGF-1 and insulin levels were not different from sham-implanted animals and tumors weight were reduced by 80%. High affinity somatostatin binding sites were found in equivalent amounts on tumors from octreotide-treated or saline-treated animals. These findings indicate that GH secretion in GC-rats is mainly derived from the tumors and independent of hypothalamic control and that octreotide reduces both GH secretion and tumor growth. We conclude that the GC-implanted rat represents a good animal model to test the antisecretory and antitrophic properties of somatostatin analogs in vivo. zyx Somatostatin (SRIH)-14 and SRIH-28 are two widely distributed peptides which induce inhibitory effects in many endocrine tissues (1) and brain (2) through at least five different G protein linked receptors (3). The native peptides are of limited clinical interest because of their very short half-life in the blood but more stable agonists, like octreotide (for review, see 4, 5), are now used frequently in the treatment of acromegaly and other neuroendo- crine tumors. Chronic treatment with SRIH analogs inhibits the growth of a variety of tumors in different animal models (6) including PRL/ACTH tumors of pituitary origin (7). However, clinically relevant analogs such as octreotide are relatively selective of the sst2, sstr3 and sstr5 subtypes only (see 2 and 3 for review). In the present work, we first quantified the expression of the five sstrs by RT-PCR in a pure GH-secreting cell line (GC). We also evaluated the effects of octreotide on GH secretion and cell proliferation from G C cells in uitro. We then tested the antisecret- ory and antitrophic effects of octreotide on GH hypersecretion, body and tumor growth in adult female Wistar-Furth rats implanted subcutaneously with GC cells that rapidly grow as solid, functional tumors (8). We also characterized the pattern of GH secretion in GC-implanted animals and tested whether GH secretion in this model was still dependent on the endogenous neurohormones GH-releasing hormone (GHRH) and SRIH by using previoulsy validated irnmunoneutralization techniques for the two neurohormones (9, 10). Results Somatostatin receptors in GC cells By quantitative RT-PCR (Fig. 1, left panel), sstr mRNAs were essentially of the sstrl and sstr2 subtypes. zyx As compared with native somatostatin, octreotide displaced only partially (55 f z 3'0, n = 3) '251-SRIH binding from GC membrane preparations (Fig. 1, right panel). IC50s were 1.18k0.86 and 0.381 0.08 nmol/L for SRIH 14 and octreotide, respectively. Effects of octreotide on GC cell growth and secretion in vitro As shown on Fig. 2, octreotide inhibited the growth and secretion of GC cells cultured in medium supplemented with 15% horse and 2.5% fetal calf serum. Maximal inhibitory effects were 57f6 Correspondmce to: Jacques Epelbaum. U.159 INSERM, 2 ter rue zyxwvutsr d'Alesia, 75014, Paris. France zyxwv 0 1995 Blackwell Science Ltd