Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase/cytosolic 5'-nucleotidase II expression ratio in primary acute myeloid leukemia cells.
Cytarabine (ara-C) is the key agent for treating acute myeloid leukemia (AML). After being transported into leukemic cells by human equilibrative nucleoside transporter 1 (hENT1), ara-C is phosphorylated to ara-C triphosphate (ara-CTP), an active metabolite, and then incorporated into DNA, thereby inhibiting DNA synthesis. Deoxycytidine kinase (dCK) and cytosolic 5'-nucleotidase II (cN-II) are associated with the production of ara-CTP. Because ara-C's cytotoxicity depends on ara-CTP production, parameters that are most related to ara-CTP formation would predict ara-C sensitivity and the clinical outcome of ara-C therapy. The present study focused on finding any correlation between the capacity to produce ara-CTP and ara-C-metabolizing factors. In vitro ara-CTP production, mRNA levels of hENT1, dCK, and cN-II, and ara-C sensitivity were evaluated in 34 blast samples from 33 leukemic patients including 26 with AML. A large degree of heterogeneity was seen in the capacity to produce ara-CTP and in mRNA levels of hENT1, dCK, and cN-II. Despite the lack of any association between each of the transcript levels and ara-CTP production, the ratio of dCK/cN-II transcript levels correlated significantly with the amount of ara-CTP among AML samples. The HL-60 cultured leukemia cell line and its three ara-C-resistant variants (HL-60/R1, HL-60/R2, HL-60/R3), which were 8-, 10-, and 500-fold more resistant than HL-60, respectively, were evaluated similarly. The dCK/cN-II ratio was again proportional to ara-CTP production and to ara-C sensitivity. The dCK/cN-II ratio may thus predict the capacity for ara-CTP production and ultimately, ara-C sensitivity in AML.
Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan. tyamauch@u-fukui.ac.jp
Takahiro
T
Yamauchi
Eiju
E
Negoro
Shinji
S
Kishi
Kazutaka
K
Takagi
Akira
A
Yoshida
Yoshimasa
Y
Urasaki
Hiromichi
H
Iwasaki
Takanori
T
Ueda
D015720:5'-Nucleotidase / Q000235:genetics*; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism*; D003561:Cytarabine / Q000378:metabolism / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000032:analysis
D033721:Equilibrative Nucleoside Transporter 1; D012333:RNA, Messenger; C438649:SLC29A1 protein, human; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D003842:Deoxycytidine Kinase; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human