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Submitted on September 22, 2006
Accepted on February 13, 2007
Department of Endocrinology & Medical Sciences and Center of Excellence for Biomedical Research (E.R., F.B., A.B., F.M., D.F.), Department of Pathology (P.D., J-L.R.), Department of Neurosurgery (G.Z., R.S.), San Martino Hospital University of Genova, Genova, Italy. Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche (A.S., P.J), Faculté de Médecine Nord, Marseille Cedex, France. Biomeasure Inc./IPSEN (M.D.C), Milford, Massachusetts, USA CLINICAL CASE SEMINAR
* To whom correspondence should be addressed. E-mail: ferone{at}unige.it.
Context: Criteria to define the response to somatostatin analogs (SSA) in acromegaly are based on biochemical control of the disease. However, the mechanisms of action of SSAs in inhibiting tumor growth and hormonal secretion are only partially understood and the two effects may occur independently.
Objective: To investigate the dissociation between anti-proliferative and anti-secretive effects of SSA in an octreotide-resistant patient displaying dramatic tumor shrinkage during primary therapy with octreotide LAR.
Design and setting: We characterized somatostatin and dopamine D2 receptor expression by immunohistochemistry and real-time RT-PCR. The effects of different receptor-selective, bi-specific analogs and chimeric somatostatin/dopamine compounds on GH secretion and cell proliferation in primary cell cultures of the tumor were assessed.
Results: The expression of sst5 and D2R was higher compared to the other receptor subtypes. GH inhibition by SS-14 and by the two chimeric somatostatin/dopamine compounds was scant, but greater than subtype-selective and sst2/sst5 bi-specific agonists. Conversely, cell growth was potently inhibited by all test substances. However, SS-14, sst2/sst5 bi-specific agonist and chimeric molecules were more potent than the other compounds.
Conclusions: The significant antiproliferative effect of octreotide seems to be related to the higher expression of sst5 and the negligible antihormonal effect to the lower expression of sst2. However, activation of multiple receptors by new analogs may produce better control of tumor cell activities. The dissociation between anti-secretive and anti-proliferative effects observed in vivo and in vitro confirms that SSAs may induce tumor shrinkage despite the lack of effect on GH secretion.
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