DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours.

OBJECTIVE: Somatostatin analogues (SSA) reduce autonomous GH secretion by activating somatostatin receptors (sst) 2 and 5 in 50-60% of acromegalic patients. However, by inhibiting insulin secretion these SSA reduce glucose tolerance. DG3173 is a novel SSA with additional binding to sst4 and low insulin-suppressing activity. We investigated the effect of DG3173, including its relation to specific tumour characteristics, on GH secretion in human somatotroph adenoma cell cultures (hSA) in comparison with Octreotide. METHODS: Twenty-seven hSA were characterised immunohistochemically for their hormone- and sst-expression, granularity and pre-surgical therapy with SSA. GH was determined in supernatants of hSA treated with DG3173 or Octreotide in time- (n=6) and dose-response (n=21) experiments. A positive response was defined as GH suppression to below 80% of baseline. RESULTS: In the dose-response experiments DG3173 suppressed GH secretion in more adenomas than Octreotide (10/21 vs 5/21), including 38% (6/16) of Octreotide non-responders. In responders the extent of GH suppression and IC(50) were comparable for both SSA. The response-rate of both SSA was higher in monohormonal vs bihormonal adenomas, yet GH declined similarly in both groups. Neither pre-surgical SSA (n=6) nor tumour morphology was related to the GH response. However, semi-quantitative analysis indicated a small but significant negative correlation between the GH response to Octreotide and the immunoreactivity scores of sst2 expression. CONCLUSIONS: DG3173 equalled Octreotide in suppressing GH secretion in hSA. Since DG3173 suppressed GH in some Octreotide-non-responsive adenomas, its clinical effectiveness will be worth testing. Moreover, its reduced insulin-suppressive potency would make it a valuable alternative to Octreotide.

Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro.

The effect of mammalian target of rapamycin (mTOR) inhibitors on pituitary tumors is unknown. Akt overexpression was demonstrated in pituitary adenomas, which may render them sensitive to the anti-proliferative effects of these drugs. The objective of the study was to evaluate the anti-proliferative efficacy of the mTOR inhibitor, rapamycin, and its orally bioavailable analog RAD001 on the GH-secreting pituitary tumor GH3 and MtT/S cells and in human GH-secreting pituitary adenomas (GH-omas) in primary cell cultures. Treatment with rapamycin or RAD001 significantly decreased the number of viable cells and cell proliferation in a dose- and time-dependent manner. This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K. Rapamycin treatment of GH3 cells induced G0/G1 cell cycle arrest. In other tumor cell types, this was attributed to a decrease in cyclin D1 levels. However, rapamycin did not affect cyclin D1 protein levels in GH3 cells. By contrast, it decreased cyclin D3 and p21/CIP, which stabilizes cyclin D/cyclin-dependent kinase 4 (cdk4) complexes. Rapamycin inhibited FCS-induced retinoblastoma phosphorylation and subsequent E2F-transcriptional activity. In response to decreased E2F activity, the expression of the E2F-regulated genes cyclin E and cdk2 was reduced. Our results showed that mTOR inhibitors potently inhibit pituitary cell proliferation, suggesting that mTOR inhibition may be a promising anti-proliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors resistant to current treatments.

Outcome of surgical intrasellar growth hormone tumor performed by a pituitary specialist surgeon in a developing country.

BACKGROUND: Acromegaly is an excessive GH secretion, which in most cases, is caused by a pituitary GH-secreting adenoma. Traditional treatment of acromegaly consists of surgery, drug therapy, and eventually radiotherapy. The aim of this retrospective study is to evaluate the results of transsphenoidal endoscopic surgery in a group of patients with intrasellar GH adenoma who were operated by a pituitary specialist surgeon. We shall then argue about the economical advantages, for the NHS of a developing country, between surgical and medical treatment. METHODS: We have analyzed data from 33 patients with intrasellar GH tumor who had been referred to the neuroendocrine department of the HGF, Brazil. The patients underwent a transsphenoidal endoscopic adenomectomy for acromegaly between 2000 and 2005. Their ages were between 20 and 67 years (mean, 44 years) at the moment of surgery. No cavernous sinus invasion was present. Follow-up was a median of 2 years (range, 12 months-6 years). RESULTS: All 33 patients had intrasellar adenoma, 84.84% of patients achieved remission by surgery. One patient was operated twice and reached hormonal normalization. Five patients still had the disease and refused a second surgery. A treatment with octreotide was started for these 5 patients and resulted in an adequate control of GH and IGF-1 levels. No patients had radiotherapy. CONCLUSION: Our patients, with intrasellar GH tumor, operated by a pituitary specialist neurosurgeon had remission rates approaching those obtained by most specialized neurosurgical centers worldwide. For equal results, our study shows that the surgical treatment is the best issue for the patient and for the NHS.