BIM-23A760, a chimeric molecule directed towards somatostatin and dopamine receptors, vs universal somatostatin receptors ligands in GH-secreting pituitary adenomas partial responders to octreotide.

Abstract

We report the comparative efficacy of a somatostatin receptor 1 and 5 subtypes (SSTR2 and SSTR5), and dopamine D2 (DAD2) compound, BIM-23A760, in suppressing GH secretion, in cell culture from human GH-secreting tumors, from patients partially responsive to long-term treatments with octreotide or lanreotide. In 18 tumors tested, the SSTR2, SSTR5, and DAD2 mRNAs were coexpressed. The SSTR2-selective analog, BIM-23197, the SSTR5-selective analog, BIM-23268, and the dopamine (DA) analog, BIM-53097, produced a mean maximal suppression of GH secretion (24 +/- 3, 20 +/- 3, and 20 +/- 3%, respectively) that was similar to that obtained with octreotide (23 +/- 3%). Nevertheless, based on individual responses, 60% of the tumors were mostly sensitive to the SSTR2 analog while 19 and 21% of the tumors were mainly responsive to the SSTR5 analog and to the DA analog, respectively. Among a series of new chimeric compounds that bind the SSTR2, SSTR5, and DAD2 receptors with variable affinities, BIM-23A760 produced greater maximal suppression of GH secretion than octreotide (38 +/- 2 vs 24 +/- 2%; p<0.03). The EC50 for BIM-23A760 was 2 pmol/l. In the presence of sulpride, the dose response inhibition of GH secretion by the trihybrid molecule, BIM-23A760, was partially reversed. The trihybrid produced also a maximal suppression of PRL greater than octreotide (74 +/- 5 vs 46 +/- 11%). When SSTRs pan inhibitors such as BIM-23A779 (binding affinity for SSTR1, SSTR2, SSTR3, SSTR5, respectively: 2.5, 0.3, 0.6, 0.6 nmol/l) or SOM230 were tested for their suppressive effects on GH secretion, they were less potent than the previous dopastatin hybrid molecule. After a brief exposure to a SSTR2-selective analog, BIM-23197, or to a DA analog, BIM-53097, the maximal GH suppression was achieved during 12 h. Under exposure to BIM-23A760, in the same conditions, maximal suppression of GH secretion lasted for 24 h. Such a longer biological effect, yet not explained, probably participates in the higher efficacy of BIM-23A760. The higher efficacy of BIM-23A760 is, at least partially, linked to its high affinity for the SSTR2 receptor subtype (IC50: 3 pmol/l). As compared to the dopastatin compound, the lower efficacy of the universal somatostatin ligands in the inhibition of GH secretion of GH-secreting tumors argues for the use of drugs targeted, according to specific receptors expression and functionality which may vary among the various classes of tumors.

• Authors: P Jaquet, G Gunz, A Saveanu, A Barlier, H Dufour, J Taylor, J Dong, S Kim, J P Moreau, M D Culler
• Journal: Journal of endocrinological investigation (J Endocrinol Invest) Vol. 28 Issue 11 Suppl International Pg. 21-7 ( 2005) ISSN: 0391-4097 [Print] Italy
• PMID: 16625841 (Publication Type: Journal Article)

Chemical References

• BIM 23197
• Oligopeptides
• Piperazines
• RNA, Messenger
• Receptors, Dopamine
• Receptors, Dopamine D2
• Receptors, Somatostatin
• Human Growth Hormone
• somatostatin receptor 5
• Prolactin
• somatostatin receptor 2
• Octreotide

Topics

• Acromegaly (drug therapy)
• Adult
• Female
• Gene Expression
• Human Growth Hormone (antagonists & inhibitors, metabolism)
• Humans
• Male
• Octreotide (therapeutic use)
• Oligopeptides (pharmacology)
• Piperazines (pharmacology)
• Pituitary Neoplasms (drug therapy, metabolism)
• Prolactin (metabolism)
• RNA, Messenger (analysis)
• Receptors, Dopamine (metabolism)
• Receptors, Dopamine D2 (genetics)
• Receptors, Somatostatin (genetics, metabolism)