ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 S28.3

Multireceptor ligands in the treatment of pituitary adenomas

Thierry Brue1,2

1Universite de la Mediterranee, Marseille, France; 2CRN2M, Centre National de la Recherche Scientifique, Marseille, France.

Using the currently available somatostatin receptor (sst) ligands octreotide and lanreotide, that are mainly sst2 agonists, about 60% of patients with acromegaly are adequately controlled. This prompted the development of new drugs targeting other sst subtypes or other receptors that are also expressed on adenomatous cells. BIM 23244 characterized by a high affinity for sst2 and sst5 had been found in vitro to allow a stronger inhibition of GH secretion than octreotide in tumors partially responsive to this treatment. The multi-sst ligand pasireotide was also found both in vitro and in vivo to suppress GH secretion more efficiently than octreotide in some patients. Preliminary data support a potential interest of this new compound in other pituitary adenomas such as corticotroph tumors. Moreover pasireotide was found to have a favorable terminal elimination half-life in humans. Some clinical findings favor a possible additive effect of dopamine D2 agonists with sst agonists in acromegaly. Hybrid drugs combining structural parts of somatostatin and dopamine were developed over the past few years. The first generation hybrid BIM23A387 displayed an improved ability to suppress GH from cultured somatotroph adenomas with an EC50 about 50 times lower than that of octreotide. Among the second generation ‘dopastatins’ presenting with high sst2 affinity and some sst5 affinity, BIM23A760 displayed the greatest efficacy over all the compounds tested in the same tumors in suppressing GH secretion. This compound also showed a significant inhibition on thymidine incorporation in GH and non functioning pituitary adenomas. These data are in line with the recent demonstration of a functional and structural cooperation of sst2 and D2 dopamine receptors. BIM23A760 was also shown to have a prolonged effect on GH suppression in vitro and in vivo in an animal model. Depending on receptor expression in each pituitary tumor type and in each particular tumor these novel multiligand drugs may prove more efficient than currently available agonists.

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