Antisense oligonucleotide-induced inhibition of adrenocorticotropic hormone release from cultured human corticotrophs.
OBJECTIVE
Available therapies for Cushing's disease are often inadequate or involve the risk of significant morbidity. Accordingly, the need arises for the development of novel treatments, especially for cases caused by corticotroph hyperplasia, a condition difficult to treat using standard therapies. In this study, the authors investigated the use of phosphorothioate antisense oligonucleotides as a potential treatment for Cushing's disease.


METHODS
Corticotrophs, obtained from a patient with Cushing's disease in whom pathological findings showed multifocal areas of corticotroph adenoma and hyperplasia, were grown in tissue culture. By assessing cell viability and using immunoradiometric assay techniques, it was determined that these cells grew autonomously and secreted adrenocorticotropic hormone (ACTH) in vitro. A fully phosphorothioated antisense oligonucleotide was constructed to be complementary to the first 25 bp of the region coding for ACTH in exon 3 of the proopiomelanocortin precursor. After incubation of the corticotrophs with liposome-coated phosphorothioate antisense oligonucleotides, a greater than 90% decrease in ACTH release was noted on Days 3 and 6, compared with nonsense-treated controls (p < 0.05).


CONCLUSIONS
Antisense oligonucleotides may prove to be a useful adjunct in treating Cushing's disease by targeting one of its fundamental problems, ACTH hypersecretion.
Frankel
B
B
Department of Neurosurgery, State University of New York Health Science Center at Syracuse, 13210, USA. frankelb@vax.cs.hscsyr.edu
Longo
S L
SL
Rodziewicz
G S
GS
Hodge
C J
CJ
D000236:Adenoma / Q000188:drug therapy* / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020029:Base Pairing; D002470:Cell Survival; D003480:Cushing Syndrome / Q000188:drug therapy; D004337:Drug Carriers; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008081:Liposomes; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D010902:Pituitary Gland / Q000187:drug effects / Q000473:pathology; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000235:genetics; D013873:Thionucleotides / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D004337:Drug Carriers; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D009946:Organothiophosphorus Compounds; D013873:Thionucleotides; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone