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PLoS One. 2016 Sep 9;11(9):e0162901. doi: 10.1371/journal.pone.0162901. eCollection 2016.

The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2.

Author information

1
Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands.
2
Department of Clinical Chemistry, laboratory Genetic Metabolic Diseases, Academic Medical Centre, Amsterdam, Netherlands.
3
Rexahn Pharmaceuticals, Inc., Rockville, Maryland, United States of America.

Abstract

Fluorocyclopentenylcytosine (RX-3117) is an orally available cytidine analog, currently in Phase I clinical trial. RX-3117 has promising antitumor activity in various human tumor xenografts including gemcitabine resistant tumors. RX-3117 is activated by uridine-cytidine kinase (UCK). Since UCK exists in two forms, UCK1 and UCK2, we investigated which form is responsible for RX-3117 phosphorylation. For that purpose we transfected A549 and SW1573 cell lines with UCK-siRNAs. Transfection of UCK1-siRNA efficiently downregulated UCK1-mRNA, but not UCK2-mRNA expression, and did not affect sensitivity to RX-3117. However, transfection of UCK2-siRNA completely downregulated UCK2-mRNA and protein and protected both A549 and SW1573 against RX-3117. UCK enzyme activity in two panels of tumor cell lines and xenograft cells correlated only with UCK2-mRNA expression (r = 0.803 and 0.915, respectively), but not with UCK1-mRNA. Moreover, accumulation of RX-3117 nucleotides correlated with UCK2 expression. In conclusion, RX-3117 is activated by UCK2 which may be used to select patients potentially sensitive to RX-3117.

PMID:
27612203
PMCID:
PMC5017758
DOI:
10.1371/journal.pone.0162901
[Indexed for MEDLINE]
Free PMC Article

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