GSE148314 A new hypomethylating agent, OR-2100, resists degradation by cytidine deaminase, leading to favorable oral absorbability and anti-leukemia effects

Contributors : Hiroshi Ureshino ; Yuki Kurahashi ; Tatsuro Watanabe ; Satoshi Yamashita ; Kazuharu Kamachi ; Yuki Fukuda-Kurahashi ; Nao Yoshida ; Naoko Hattori ; Yoshihiro Hayashi ; Kaoru Tohyama ; Seiji Okada ; Hironori Harada ; Toshikazu Ushijima ; Shinya KimuraSeries Type : Methylation profiling by genome tiling arrayOrganism : Homo sapiensDNA methyltransferase inhibitors have improved the prognosis of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). However, these agents must be administered intravenously or subcutaneously because they are degraded easily by cytidine deaminase (CDA). OR2100 (OR21), an oligonucleotide comprising decitabine nucleoside 5'-O-trisilylate, resists degradation by CDA. Direct duodenal administration led to high plasma concentrations of OR21 in a cynomolgus monkey model. Transcriptome and methylome analysis of MDS and AML cell lines revealed that OR21 enriched expression of genes associated with tumour suppression, cell differentiation, and immune system processes via alteration of regional promoter methylation. Conversely, immune system process pathways were downregulated in azacytidine-resistant AML cells, indicating that these pathways play a pivotal role in the action of hypomethylating agents. Both in vivo and in vitro, OR21 showed anti-leukaemia effects against MDS and AML cells (including AZA-resistant), and a better safety profile than decitabine. These results suggest that OR21 is a candidate drug for a pha...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by genome tiling array Homo sapiens Source Type: research