Endocrine Abstracts (2008) 16 S20.1

sst2 gene transfer restores the somatostatin agonist sensitivity of human resistant pituitary adenomas, in vitro

Julie Acunzo1, Catherine Roche1, Sylvie Thirion1, Ginette Gunz1, Alexandru Saveanu2, Anne Laure Germanetti2, Alessandra Fusco1, Bettina Couderc3, Alain Enjalbert1 & Anne Barlier1

1Centre de Recherche en Neurophysiologie et Neurobiologie de Marseille, Marseille, France; 2Laboratoire de Biochimie et Biologie Moléculaire, AP-HM, Marseille, France; 3INSERM U563 Institut Claudius Regaud, Toulouse, France.

Somatotroph adenoma represent 20% of pituitary adenoma. Although often considered as benign, they can induce serious neurological and metabolic complications. GH hypersecretion can be inhibited by somatostatin agonists such as octreotide or lanreotide. However, some GH levels reach normal values in only 50% of treated patiens. The decreased sensitivity to the somatostatin agonists was shown to be related to a lower expression of the sst2 gene.

To reverse the octreotide resistance, our aim was to reintroduce sst2 gene in human pituitary adenoma cells in vitro. Sst2 gene transfer was done by adenoviral vector (Ad-sst2). Adenoviral vector expressing eGFP (Ad-eGFP) was used as control vector. The transgene sst2 expression was followed by real-time PCR and by immunocytochemistry. The sst2 mRNA expression increased to 100 fold after infection. In resistant tumors, the sst2 immunostaining was observed at the membrane in the transduced cells whereas the sst2 staining was intracellular in the control cells. In somatotroph adenoma cells, sst2 gene transfer induced not only a decrease in hormonal secretion but also a decrease in cell number by an apoptotic effect, using a caspase-dependant pathway. The decrease in GH secretion was due, at least in part to the decrease in hormonal expression. Five days after 5MOI adenoviral infection, sst2 gene transfer improved the octreotide sensitivity. The dose-related inhibition of GH release was moved toward the lower concentrations. A decrease in EC50 was observed (about 1 log) in all tumours. Moreover, the maximal GH suppression under octreotide increased in resistant ones. In conclusion, sst2 gene may constitute a new therapeutic gene for somatotroph adenoma resistant to the somatostatin agonists.