Abstract
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, EC(50) 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 therapeutic strategies in treatment combined with somatostatin analogues.
Highlights
Peptide-targeted therapy is a hot topic in Endocrine Oncology, with strong effect for both diagnostic and therapeutic strategies
To follow up sst2 transgene expression, sst2 mRNA was quantified by real-time PCR in 5 multiplicity of infection (MOI) Ad-sst2–infected cells, compared with 5 MOI Ad-eGFP–infected cells and to noninfected cells (Table 2)
We showed that sst2 gene transfer alone induced a strong decrease in cell viability of human somatotroph and lactotroph adenomatous cells in vitro
Summary
Peptide-targeted therapy is a hot topic in Endocrine Oncology, with strong effect for both diagnostic and therapeutic strategies. The discovery of somatostatin analogues such as octreotide and lanreotide dramatically modified the treatment of endocrine. We showed that the level of sst expression is correlated with the agonist sensitivity. These growth hormone (GH)-secreting tumors represent f15% of pituitary adenomas [2]. A strong correlation exists between the level of sst mRNA expression and the percentage of GH inhibition under octreotide or native somatostatin [4, 5], no relationship has been observed between sst mRNA level and somatostatin sensitivity [5]. The sst receptor is the main receptor mediating somatostatin-induced inhibition of GH secretion [6, 7]
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