New SRIF analogs in the control of human pituitary adenomas: perspectives

SRIF receptor (sst) subtypes expressed on the different neuroendocrine tumors are the basis for treatment of such tumors with SRIF analogues. Although the drugs of reference, octreotide and lanreotide, are widely used in the treatment of acromegaly, their long-term administration allows an effective control of both GH hypersecretion and IGF-I levels in about 60% of the patients. This variable sensitivity is related to a significant loss of the sst subtype 2 (sst2) in the octreotide partial responder acromegalic patients. Such a decrease is rescued, in these tumors, by an overexpression of the sst5. Further, all GH-secreting adenomas coexpress the D2 dopamine receptor, which also mediates the inhibitory effect of dopamine agonists on GH secretion in acromegalic tumors. Such specific profiles of receptor expression in this class of neuroendocrine tumors led to the development of new ligand molecules directed towards sst2 + sst5 receptors, sst1 + sst2 + sst3 + sst5 receptors, or sst2 + dopamine D2 receptors. These bi- or multivalents ligands proved, in cell culture studies, more effective than their single components for inhibiting GH and PRL secretion. This review covers the data recently issued using such hybrid or chimeric compounds. The mechanism(s) by which such ligands may act are yet unknown. One possible explanation of their increased potency could be through their ability to induce oligodimerization of the receptors at the cell membrane level, and modify, in a ligands-specific manner, the subsequent trafficking and recycling of the receptors. New details from the literature are reviewed, supporting the importance of such ligands into the agonist-dependant control of G-protein-coupled receptors oligomerization.