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Somatostatin Receptor sst2 Decreases Cell Viability and Hormonal Hypersecretion and Reverses Octreotide Resistance of Human Pituitary Adenomas

¹ Center of Research in Neurobiology-Neurophysiology of Marseille, UMR 6231 Centre National de la Recherche Scientifique, Institut Fédératif Jean-Roche, University of Méditerranée, ² Laboratory of Biochemistry and Molecular Biology, ³ Laboratory of Neuropathology, Departments of ⁴ Neurosurgery and ⁵ Endocrinology, Centre Hospitalo-Universitaire Timone, Marseille, France; ⁶ EA 3035 Institut Claudius Regaud, University of Toulouse, Toulouse, France; and ⁷ University of Lyon 1, ISPB, UPSP 2007.03.135 TRI2B, Hôpital Edouard Herriot, Fédération de Biochimie, Hospices Civils de Lyon, Lyon, France

Requests for reprints: Anne Barlier, Laboratoire CRN2M UMR 6231-CNRS, Institut Jean-Roche, Faculté de Médecine Nord, Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France. Phone: 33491698917; Fax: 33-491698920; E-mail: anne.barlier{at}univmed.fr.

Key Words: pituitary adenomas • somatostatin receptor sst2 • somatostatin analogues • gene therapy • tumorigenicity

In human somatotroph adenomas, growth hormone (GH) hypersecretion can be inhibited by somatostatin analogues such as octreotide. Unfortunately, serum GH levels reach normal values in only 60% of treated patients. The decreased sensitivity to octreotide is strongly related to a lower expression of somatostatin receptor sst2. In this present study, the sst2 gene was transferred by an adenoviral vector (Ad-sst2) in human somatotroph (n = 7) and lactotroph (n = 2) adenomas in vitro. Sst2 mRNA levels and sst2 immunostaining dramatically increased after infection. Ten days after infection at 20 multiplicity of infection (MOI), sst2 gene transfer decreased cell viability from 19% to 90% by caspase-dependent apoptosis. At low viral doses (5 MOI), Ad-sst2 decreased GH or prolactin (PRL) basal secretion and mRNA expression. Somatotroph tumors were classified in three groups according to their octreotide sensitivity. Four days after infection by 5 MOI Ad-sst2, the maximal GH suppression by octreotide increased from 31% to 57% in the octreotide partially resistant group and from 0% to 27% in the resistant ones. In the octreotide-sensitive group, EC₅₀ values significantly decreased from 1.3 x 10^–11 to 6.6 x 10^–13 mol/L without improving maximal GH suppression. Finally, lactotroph tumors, nonresponding to octreotide in basal conditions, became octreotide sensitive with a maximal PRL suppression of 43% at 10^–8 mol/L. Therefore, sst2 reexpression is able to improve octreotide sensitivity. Sst2 gene transfer may open new theapeutic strategies in treatment combined with somatostatin analogues. [Cancer Res 2008;68(24):10163–70]