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Oral decitabine reactivates expression of the methylated γ‐globin gene in Papio anubis
Author(s) -
Lavelle Donald,
Chin Janet,
Vaitkus Kestis,
Redkar Sanjeev,
Phiasivongsa Pasit,
Tang Chunlin,
Will Roselle,
Hankewych Maria,
Roxas Bryan,
Singh Mahipal,
Saunthararajah Yogen,
DeSimone Joseph
Publication year - 2007
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.21020
Subject(s) - decitabine , cladribine , pharmacology , myelodysplastic syndromes , dna methyltransferase , dna methylation , medicine , cancer research , biology , gene expression , gene , immunology , bone marrow , genetics
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 γ‐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 γ‐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 ϵ‐ and γ‐globin gene promoters, and increases histone acetylation of these promoters in baboons ( Papio anubis ). Am. J. Hematol., 2007. Published 2007 Wiley‐Liss, Inc.