The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2.
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.
Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands.
Dzjemma
D
Sarkisjan
Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands.
Joris R
JR
Julsing
Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands.
Kees
K
Smid
Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands.
Daniël
D
de Klerk
Department of Clinical Chemistry, laboratory Genetic Metabolic Diseases, Academic Medical Centre, Amsterdam, Netherlands.
André B P
AB
van Kuilenburg
Department of Clinical Chemistry, laboratory Genetic Metabolic Diseases, Academic Medical Centre, Amsterdam, Netherlands.
Rutger
R
Meinsma
Rexahn Pharmaceuticals, Inc., Rockville, Maryland, United States of America.
Young B
YB
Lee
Rexahn Pharmaceuticals, Inc., Rockville, Maryland, United States of America.
Deog J
DJ
Kim
Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands.
Godefridus J
GJ
Peters
D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003562:Cytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012044:Regression Analysis; D015203:Reproducibility of Results; D013379:Substrate Specificity / Q000187:drug effects; D014162:Transfection; D014541:Uridine Kinase / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000589325:fluorocyclopentenylcytosine; D003562:Cytidine; D014541:Uridine Kinase