TY  - JOUR
AU  - Öz, Aliye Simin
AU  - Raddatz, Günter
AU  - Rius Montraveta, Maria
AU  - Blagitko-Dorfs, Nadja
AU  - Lübbert, Michael
AU  - Maercker, Christian
AU  - Lyko, Frank
TI  - Quantitative determination of decitabine incorporation into DNA and its effect on mutation rates in human cancer cells.
JO  - Nucleic acids symposium series
VL  - 42
IS  - 19
SN  - 1362-4962
CY  - Oxford
PB  - Oxford Univ. Press44364
M1  - DKFZ-2017-00618
SP  - e152 - e152
PY  - 2014
AB  - Decitabine (5-aza-2'-deoxycytidine) is a DNA methyltransferase inhibitor and an archetypal epigenetic drug for the therapy of myeloid leukemias. The mode of action of decitabine strictly depends on the incorporation of the drug into DNA. However, DNA incorporation and ensuing genotoxic effects of decitabine have not yet been investigated in human cancer cell lines or in models related to the approved indication of the drug. Here we describe a robust assay for the quantitative determination of decitabine incorporation rates into DNA from human cancer cells. Using a panel of human myeloid leukemia cell lines we show appreciable amounts of decitabine incorporation that closely correlated with cellular drug uptake. Decitabine incorporation was also detectable in primary cells from myeloid leukemia patients, indicating that the assay is suitable for biomarker analyses to predict drug responses in patients. Finally, we also used next-generation sequencing to comprehensively analyze the effects of decitabine incorporation on the DNA sequence level. Interestingly, this approach failed to reveal significant changes in the rates of point mutations and genome rearrangements in myeloid leukemia cell lines. These results indicate that standard rates of decitabine incorporation are not genotoxic in myeloid leukemia cells.
KW  - Antimetabolites, Antineoplastic (NLM Chemicals)
KW  - DNA, Neoplasm (NLM Chemicals)
KW  - decitabine (NLM Chemicals)
KW  - Azacitidine (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25159616
C2  - pmc:PMC4231731
DO  - DOI:10.1093/nar/gku775
UR  - https://inrepo02.dkfz.de/record/120030
ER  -