a comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines阿扎胞苷的比较,在急性髓系白血病细胞系decitabine活动.pdfVIP

A Comparison of Azacitidine and Decitabine Activities in Acute Myeloid Leukemia Cell Lines 1 1 1 2 1 Paul W. Hollenbach , Aaron N. Nguyen , Helen Brady , Michelle Williams , Yuhong Ning , Normand 1 2 1 1 1 Richard , Leslie Krushel , Sharon L. Aukerman , Carla Heise , Kyle J. MacBeth * 1 Celgene Corporation, San Francisco, California, United States of America, 2 Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America Abstract Background: The cytidine nucleoside analogs azacitidine (AZA) and decitabine (DAC) are used for the treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Few non-clinical studies have directly compared the mechanisms of action of these agents in a head-to-head fashion, and the agents are often viewed as mechanistically similar DNA hypomethylating agents. To better understand the similarities and differences in mechanisms of these drugs, we compared their in vitro effects on several end points in human AML cell lines. Methodology/Principal Findings: Both drugs effected DNA methyltransferase 1 depletion, DNA hypomethylation, and DNA damage induction, with DAC showing equivalent activity at concentrations 2- to 10-fold lower than AZA. At concentrations above 1 mM, AZA had a greater effect than DAC on reducing cell viability. Both drugs increased the sub-G1 fraction and apoptosis markers, with AZA decreasing all cell cycle phases and DAC causing an increase in G2-M. Total protein synthesis was reduced only by AZA, and drug-modulated gene expression profiles were largely non-overlapping.