Somatostatin receptor sst2 decreases cell viability and hormonal hypersecretion and reverses octreotide resistance of human pituitary adenomas.

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.

• Authors: Julie Acunzo, Sylvie Thirion, Catherine Roche, Alexandru Saveanu, Ginette Gunz, Anne Laure Germanetti, Bettina Couderc, Richard Cohen, Dominique Figarella-Branger, Henry Dufour, Thierry Brue, Alain Enjalbert, Anne Barlier
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 24 Pg. 10163-70 (Dec 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 19074883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• RNA, Messenger
• Receptors, Somatostatin
• Human Growth Hormone
• Prolactin
• somatostatin receptor 2
• Octreotide

Topics

• Adenoviridae (genetics)
• Antineoplastic Agents, Hormonal (pharmacology)
• Cell Survival (physiology)
• Drug Resistance, Neoplasm
• Growth Hormone-Secreting Pituitary Adenoma (drug therapy, genetics, metabolism)
• Human Growth Hormone (biosynthesis, genetics, metabolism)
• Humans
• Immunohistochemistry
• Octreotide (pharmacology)
• Pituitary Neoplasms (drug therapy, genetics, metabolism)
• Prolactin (biosynthesis, genetics, metabolism)
• Prolactinoma (drug therapy, genetics, metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Receptors, Somatostatin (biosynthesis, genetics)
• Transduction, Genetic
• Transgenes