S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis)

Journal of Translational Medicine

Research

Yogen Saunthararajah¹  Joseph DeSimone²  Donald Lavelle²  Virryan Banzon²  Kestis Vaitkus²  Mahipal Singh³  Sanjeev Redkar⁴  David Bearss⁴  Pasit Phiasivongsva⁴  Sarath Kanekal⁴  Roger Inloes⁴  Chongtie Shi⁴ 

[1] Department of Medicine, University of Illinois at Chicago, 840 S. Wood St, 60612-7323, Chicago, Illinois, USA;Department of Hematologic and Blood Disorders, Cleveland Clinic, 9500 Euclid St, 44195, Cleveland, Ohio, USA;Department of Medicine, University of Illinois at Chicago, 840 S. Wood St, 60612-7323, Chicago, Illinois, USA;Jesse Brown VA Medical Center, 820 S. Damen Ave, 60612, Chicago, Illinois, USA;Department of Medicine, University of Illinois at Chicago, 840 S. Wood St, 60612-7323, Chicago, Illinois, USA;Jesse Brown VA Medical Center, 820 S. Damen Ave, 60612, Chicago, Illinois, USA;Department of Animal Science/Molecular Biology, Agricultural Research Station, Fort Valley State University, 31030-4313, Fort Valley, Georgia, USA;SuperGen, Inc, 4140 Dublin Blvd, 94568, Dublin, California, USA;

关键词: Sickle Cell Disease;    Decitabine;    Cytidine Deaminase;    Fetal Hemoglobin;    Bisulfite Sequence Analysis;   

DOI  :  10.1186/1479-5876-8-92

 received in 2010-01-11, accepted in 2010-10-08,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundS110 is a novel dinucleoside analog that could have advantages over existing DNA methyltransferase (DNMT) inhibitors such as decitabine. A potential therapeutic role for S110 is to increase fetal hemoglobin (HbF) levels to treat β-hemoglobinopathies. In these experiments the effect of S110 on HbF levels in baboons and its ability to reduce DNA methylation of the γ-globin gene promoter in vivo were evaluated.MethodsThe effect of S110 on HbF and γ-globin promoter DNA methylation was examined in cultured human erythroid progenitors and in vivo in the baboon pre-clinical model. S110 pharmacokinetics was also examined in the baboon model.ResultsS110 increased HbF and reduced DNA methylation of the γ-globin promoter in human erythroid progenitors and in baboons when administered subcutaneously. Pharmacokinetic analysis was consistent with rapid conversion of S110 into the deoxycytosine analog decitabine that binds and depletes DNA.ConclusionS110 is rapidly converted into decitabine, hypomethylates DNA, and induces HbF in cultured human erythroid progenitors and the baboon pre-clinical model.

【 授权许可】

CC BY   
© Lavelle et al; licensee BioMed Central Ltd. 2010