Table of Contents
Chemotherapy Research and Practice
Volume 2011 (2011), Article ID 965826, 9 pages
http://dx.doi.org/10.1155/2011/965826
Research Article

Development of an Oral Form of Azacytidine: 𝟐 𝟑 𝟓 Triacetyl-5-Azacytidine

1Nevada Cancer Institute, One Breakthough Way, Las Vegas, NV 89135, USA
2St. Jude Children's Research Hospital, Memphis, TN 38105, USA
3The Hong Kong Polytechnic University, Kowloon, Hong Kong

Received 12 July 2011; Revised 14 September 2011; Accepted 21 September 2011

Academic Editor: G. J. Peters

Copyright © 2011 Amy Ziemba et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Myelodysplastic syndromes (MDSs) represent a group of incurable stem-cell malignancies which are predominantly treated by supportive care. Epigenetic silencing through promoter methylation of a number of genes is present in poor-risk subtypes of MDS and often predicts transformation to acute myelogenous leukemia (AML). Azacitidine and decitabine, two FDA-approved DNA methyltransferase (DNMT) inhibitors, are able to improve overall response although their oral bioavailability complicates their clinical use. This study evaluated 2 , 3 , 5 -triacetyl-5-azacitidine (TAC) as a potential prodrug for azacitidine. The prodrug demonstrated significant pharmacokinetic improvements in bioavailability, solubility, and stability over the parent compound. In vivo analyses indicated a lack of general toxicity coupled with significantly improved survival. Pharmacodynamic analyses confirmed its ability to suppress global methylation in vivo. These data indicate that esterified nucleoside derivatives may be effective prodrugs for azacitidine and encourages further investigation of TAC into its metabolism, activity, and possible clinical evaluation.