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@ARTICLE{z:120030,
author = {A. S. Öz$^*$ and G. Raddatz$^*$ and M. Rius Montraveta$^*$
and N. Blagitko-Dorfs and M. Lübbert and C. Maercker$^*$
and F. Lyko$^*$},
title = {{Q}uantitative determination of decitabine incorporation
into {DNA} and its effect on mutation rates in human cancer
cells.},
journal = {Nucleic acids symposium series},
volume = {42},
number = {19},
issn = {1362-4962},
address = {Oxford},
publisher = {Oxford Univ. Press44364},
reportid = {DKFZ-2017-00618},
pages = {e152 - e152},
year = {2014},
abstract = {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.},
keywords = {Antimetabolites, Antineoplastic (NLM Chemicals) / DNA,
Neoplasm (NLM Chemicals) / decitabine (NLM Chemicals) /
Azacitidine (NLM Chemicals)},
cin = {A130 / W110},
ddc = {540},
cid = {I:(DE-He78)A130-20160331 / I:(DE-He78)W110-20160331},
pnm = {311 - Signalling pathways, cell and tumor biology
(POF3-311)},
pid = {G:(DE-HGF)POF3-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25159616},
pmc = {pmc:PMC4231731},
doi = {10.1093/nar/gku775},
url = {https://inrepo02.dkfz.de/record/120030},
}