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

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Title: S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis)
Author(s): Lavelle, Donald; Saunthararajah, Yogen; Vaitkus, Kestis; Singh, Mahipal; Banzon, Virryan; Phiasivongsva, Pasit; Redkar, Sanjeev; Kanekal, Sarath; Bearss, David; Shi, Chongtie; Inloes, Roger; DeSimone, Joseph
Subject(s): S110 fetal hemoglobin
Abstract: Background: S110 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 b-hemoglobinopathies. In these experiments the effect of S110 on HbF levels in baboons and its ability to reduce DNA methylation of the g-globin gene promoter in vivo were evaluated. Methods: The effect of S110 on HbF and g-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. Results: S110 increased HbF and reduced DNA methylation of the g-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. Conclusion: S110 is rapidly converted into decitabine, hypomethylates DNA, and induces HbF in cultured human erythroid progenitors and the baboon pre-clinical model.
Issue Date: 2010-10-08
Publisher: BioMed Central
Citation Info: Lavelle, D., Saunthararajah, Y., Vaitkus, K., Singh, M., Banzon, V., Phiasivongsva, P., Redkar, S., Kanekal, S., Bearss, D., Shi, C., Inloes, R., & Desimone, J. 2010. S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis). Journal of Translational Medicine, 8: 92. DOI: 10.1186/1479-5876-8-92
Type: Article
Description: The original version is available through BioMed Central at DOI: 10.1186/1479-5876-8-92. © 2010 Lavelle et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which (http://creativecommons.org/licenses/by/2.0), permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
URI: http://hdl.handle.net/10027/7615
ISSN: 1479-5876
Sponsor: This work was supported by NIH.
Date Available in INDIGO: 2011-05-12
 

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