Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study.
Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for alpha-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9+/-2.6 copy/copy beta-glucuronidase; mean+/-s.e.m.), when compared with sstr3 and sstr2 (0.6+/-1.0 and 0.3+/-0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [3H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC50=1.2 pM and Emax=-33.6+/-3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.
Department of Oncology, Biology and Genetics, University of Genova, Viale Benedetto XV, 2, 16132 Genova, Italy. tullio.florio@unige.it
Tullio
T
Florio
Federica
F
Barbieri
Renato
R
Spaziante
Gianluigi
G
Zona
Leo J
LJ
Hofland
Peter M
PM
van Koetsveld
Richard A
RA
Feelders
Günter K
GK
Stalla
Marily
M
Theodoropoulou
Michael D
MD
Culler
Jesse
J
Dong
John E
JE
Taylor
Jacques-Pierre
JP
Moreau
Alexandru
A
Saveanu
Ginette
G
Gunz
Henry
H
Dufour
Philippe
P
Jaquet
D000236:Adenoma / Q000188:drug therapy* / Q000473:pathology*; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000077465:Cabergoline; D002455:Cell Division / Q000187:drug effects; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000494:pharmacology; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics; D017481:Receptors, Somatostatin / Q000235:genetics; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D018492:Dopamine Antagonists; D004873:Ergolines; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; D014316:Tritium; D013004:Somatostatin; D013469:Sulpiride; C093733:somatostatin receptor 2; C531242:TBR-760; D000077465:Cabergoline; D015282:Octreotide; D013936:Thymidine; D004298:Dopamine