Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy.
OBJECTIVE
This study compared the potency of a somatostatin receptor (sstr)2-sstr5 analog, BIM-23244, of an sstr2-dopamine D2 receptor (sstr2-DAD2) molecule, BIM-23A387 and of new somatostatin-dopamine chimeric molecules with differing, enhanced affinities for sstr2, sstr5 and DAD2, BIM-23A758, BIM-23A760 and BIM-23A761, to suppress GH and prolactin (PRL) from 18 human GH adenomas that are partially responsive to octreotide or lanreotide.


METHODS
The sstr2, sstr5 and DAD2 mRNA levels were determined by RT-PCR. The effect of drugs was tested in cell cultures at various concentrations.


RESULTS
In all tumors, the sstr2, sstr5 and DAD2 mRNA levels were coexpressed (mean levels+/-s.e.m. 0.4+/-0.1, 5.3+/-1.9 and 2.0+/-0.4 copy/copy beta-glucuronidase). In 13 tumors, the maximal suppression of GH secretion produced by BIM-23A387 (30+/-3%) and BIM-23244 (28+/-3%) was greater than that produced by octreotide (23+/-3%). In six out of 13 tumors, BIM-23A758, BIM-23A760 and BIM- 23A761 produced greater maximal suppression of GH secretion than octreotide (33+/-5, 38+/-2 and 41+/-2 vs 24+/-2%). Their EC(50) values were 10, 2 and 4 pmol/l. BIM-23A761 was more effective than BIM-23A387 in GH suppression (41+/-2 vs 32+/-4%). The new chimeric molecules produced maximal PRL suppression greater than octreotide (62+/-8 to 74+/-5 vs 46+/-11%).


CONCLUSIONS
Novel dopamine-somatostatin chimeric molecules with differing, enhanced activity at sstr2, sstr5 and DAD2, consistently produced significatly greater suppression of GH and PRL than either octreotide or single-receptor-interacting ligands in tumors from patients classified as only partially responsive to octreotide therapy. The higher efficacy of the chimeric compounds was, at least partially, linked to their high affinity for sstr2 (IC50 1-10 pmol/l). The other mechanisms by which such molecules produce an enhanced inhibition of GH remain to be elucidated.
Jaquet
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P
Interactions Cellulaires Neuroendocriniennes, UMR6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France. jaquet.p@jean-roche.univ.mrs.fr
Gunz
G
G
Saveanu
A
A
Dufour
H
H
Taylor
J
J
Dong
J
J
Kim
S
S
Moreau
J-P
JP
Enjalbert
A
A
Culler
M D
MD
D000172:Acromegaly / Q000097:blood / Q000188:drug therapy; D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm; D005260:Female; D019382:Human Growth Hormone / Q000097:blood / Q000378:metabolism; D006801:Humans; D008297:Male; D015282:Octreotide / Q000008:administration & dosage; D010911:Pituitary Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D011388:Prolactin / Q000097:blood / Q000378:metabolism; D015175:Prolactinoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017448:Receptors, Dopamine D2 / Q000008:administration & dosage* / Q000235:genetics; D017481:Receptors, Somatostatin / Q000008:administration & dosage* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; C423390:BIM-23244; C577073:BIM-23A761; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D011993:Recombinant Fusion Proteins; D019382:Human Growth Hormone; D013004:Somatostatin; C094573:somatostatin receptor 5; D011388:Prolactin; C093733:somatostatin receptor 2; C531242:TBR-760; D015282:Octreotide; D004298:Dopamine