Oral decitabine reactivates expression of the methylated gamma-globin gene in Papio anubis.
Am J Hematol
; 82(11): 981-5, 2007 Nov.
Article
in En
| MEDLINE
| ID: mdl-17696208
ABSTRACT
The silencing of tumor suppressor genes associated with increased DNA methylation of the promoter regions is a frequent observation in many forms of cancer. Reactivation of these genes using pharmacological inhibitors of DNA methyltransferase such as 5-aza-2'-deoxycytidine (decitabine) is a worthwhile therapeutic goal. The effectiveness and tolerability of low-dose intravenous and subcutaneous decitabine regimens to demethylate and reactivate expression of the methylated gamma-globin gene in baboons and in patients with sickle cell disease led to successful trials of low-dose regimens of this drug in patients with myelodysplastic syndrome. Since these low-dose regimens are well-tolerated with minimal toxicity, they are suitable for chronic dosing to maintain promoter hypomethylation and expression of target genes. The development of an orally administered therapy using DNA methyltransferase inhibitors would facilitate such chronic approaches to therapy. We tested the ability of decitabine and a new salt derivative, decitabine mesylate, to reactivate the methylated gamma-globin gene in baboons when administered orally. Our results demonstrate that oral administration of these drugs at doses 17-34 times optimal subcutaneous doses of decitabine reactivates fetal hemoglobin, demethylates the epsilon- and gamma-globin gene promoters, and increases histone acetylation of these promoters in baboons (Papio anubis).
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Azacitidine
/
Fetal Hemoglobin
/
DNA Modification Methylases
/
DNA Methylation
/
Gene Silencing
Limits:
Animals
Language:
En
Journal:
Am J Hematol
Year:
2007
Document type:
Article
Affiliation country:
United States