Rapid pituitary tumor shrinkage with dissociation between antiproliferative and antisecretory effects of a long-acting octreotide in an acromegalic patient.
BACKGROUND
Criteria to define the response to somatostatin (SS) 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
The objective of the study was to investigate the dissociation between antiproliferative and antisecretive effects of SSA in an octreotide-resistant patient displaying dramatic tumor shrinkage during primary therapy with octreotide LAR.


METHODS
We characterized somatostatin and dopamine D(2) receptor expression by immunohistochemistry and real-time RT-PCR. The effects of different receptor-selective, bispecific 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 SS receptor subtypes (sst)(5) and D(2) receptor was higher, compared with the other receptor subtypes. GH inhibition by SS-14 and the two chimeric somatostatin/dopamine compounds was scant but greater than subtype-selective and sst(2)/sst(5) bispecific agonists. Conversely, cell growth was potently inhibited by all test substances. However, SS-14, sst(2)/sst(5) bispecific 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 sst(5) and the negligible antihormonal effect to the lower expression of sst(2). However, activation of multiple receptors by new analogs may produce better control of tumor cell activities. The dissociation between antisecretive and antiproliferative effects observed in vivo and in vitro confirms that SSAs may induce tumor shrinkage despite the lack of effect on GH secretion.
Resmini
Eugenia
E
Department of Endocrinology and Metabolism, University of Genova, Viale Benedetto XV 6, 16132 Genoa, Italy.
Dadati
Patrizia
P
Ravetti
Jean-Luis
JL
Zona
Gianluigi
G
Spaziante
Renato
R
Saveanu
Alexandru
A
Jaquet
Philippe
P
Culler
Michael D
MD
Bianchi
Federico
F
Rebora
Alberto
A
Minuto
Francesco
F
Ferone
Diego
D
D000172:Acromegaly / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000239:Adenoma, Acidophil / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000077465:Cabergoline; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003692:Delayed-Action Preparations; D004873:Ergolines / Q000627:therapeutic use; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008854:Microscopy, Electron; D015282:Octreotide / Q000008:administration & dosage / Q000627:therapeutic use*; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin / Q000235:genetics; D013936:Thymidine / Q000378:metabolism
D003692:Delayed-Action Preparations; D004873:Ergolines; D012333:RNA, Messenger; D019382:Human Growth Hormone; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D000077465:Cabergoline; D015282:Octreotide; D013936:Thymidine