GSE141677 A new hypomethylating agent, OR-2100, resists degradation by cytidine deaminase, leading to favourable oral absorbability and ant-leukaemia effects

Contributors : Hiroshi Ureshino ; Yuki Kurahashi ; Tatsuro Watanabe ; Kazuharu Kamachi ; Yuki Fukuda-Kurahashi ; Nao Yoshida ; Naoko Hattori ; Yoshihiro Hayashi ; Kaoru Tohyama ; Seiji Okada ; Hironori Harada ; Toshikazu Ushijima ; Shinya KimuraSeries Type : Expression profiling by 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. Microarray analysis of MDS and AML cell lines revealed that OR21 enriched expression of genes associated with tumour suppression, cell differentiation, and immune system processes. 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, and a better safety profile than decitabine. These results suggest that OR21 is a candidate drug for a phase 1 study as an alternative to DAC.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Homo sapiens Source Type: research