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Status |
Public on Apr 09, 2020 |
Title |
A new hypomethylating agent, OR-2100, resists degradation by cytidine deaminase, leading to favorable oral absorbability and anti-leukemia effects |
Organism |
Homo sapiens |
Experiment type |
Methylation profiling by genome tiling array
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Summary |
DNA 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 phase 1 study as an alternative to DAC.
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Overall design |
To investigate the effect of OR2100, comparing the gene expressions between OR2100 treated cells and untreated cells.
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Contributor(s) |
Ureshino H, Kurahashi Y, Watanabe T, Yamashita S, Kamachi K, Fukuda-Kurahashi Y, Yoshida N, Hattori N, Hayashi Y, Tohyama K, Okada S, Harada H, Ushijima T, Kimura S |
Citation(s) |
34045225 |
Submission date |
Apr 08, 2020 |
Last update date |
Jan 13, 2023 |
Contact name |
Shinya Kimura |
E-mail(s) |
shkimu@cc.saga-u.ac.jp
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Phone |
+81952342366
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Organization name |
Saga University
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Department |
Drug Discovery and Biomedical Sciences, Faculty of Medicine
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Street address |
5-1-1 Nabeshima
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City |
Saga |
ZIP/Postal code |
849-8501 |
Country |
Japan |
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Platforms (1) |
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Samples (15)
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Relations |
BioProject |
PRJNA623877 |
Supplementary file |
Size |
Download |
File type/resource |
GSE148314_OR21forMDS_normalized_data.txt.gz |
69.6 Mb |
(ftp)(http) |
TXT |
GSE148314_RAW.tar |
161.2 Mb |
(http)(custom) |
TAR |
GSE148314_non-normalized_data.txt.gz |
174.0 Mb |
(ftp)(http) |
TXT |
Processed data are available on Series record |
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