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

Abstract

<div>Abstract<p>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 <i>sst2</i> gene was transferred by an adenoviral vector (Ad-sst2) in human somatotroph (<i>n</i> = 7) and lactotroph (<i>n</i> = 2) adenomas <i>in vitro</i>. Sst2 mRNA levels and sst2 immunostaining dramatically increased after infection. Ten days after infection at 20 multiplicity of infection (MOI), <i>sst2</i> 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, EC<sub>50</sub> values significantly decreased from 1.3 × 10<sup>−11</sup> to 6.6 × 10<sup>−13</sup> 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<sup>−8</sup> mol/L. Therefore, sst2 reexpression is able to improve octreotide sensitivity. <i>Sst2</i> gene transfer may open new theapeutic strategies in treatment combined with somatostatin analogues. [Cancer Res 2008;68(24):10163–70]</p></div>