BACKGROUND/AIM: Clofarabine is transported into leukemic cells via the equilibrative nucleoside transporters (hENT) 1 and 2 and the concentrative nucleoside transporter (hCNT) 3, then phosphorylated by deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) to an active triphosphate metabolite. Cytarabine uses hENT1 and dCK for its activation. We hypothesized that cytarabine-resistant leukemia cells retain sensitivity to clofarabine. MATERIALS AND METHODS: Human myeloid leukemia HL-60 cells and cytarabine-resistant variant HL/ara-C20 cells were used in the present study. RESULTS: Despite 20-fold cytarabine resistance, the HL/ara-C20 cells exhibited only a 6-fold resistance to clofarabine compared to HL-60 cells. The intracellular concentration of the triphosphate metabolite of cytarabine was reduced to 1/10, and that of clofarabine was halved in the HL/ara-C20 cells. hENT1 and dCK were reduced, but hCNT3 and dGK were not altered in the HL/ara-C20 cells, which might contribute to their retained capability to produce intracellular triphosphate metabolite of clofarabine. CONCLUSION: Clofarabine was cytotoxic to leukemia cells that were resistant to cytarabine.
BACKGROUND/AIM: Clofarabine is transported into leukemic cells via the equilibrative nucleoside transporters (hENT) 1 and 2 and the concentrative nucleoside transporter (hCNT) 3, then phosphorylated by deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) to an active triphosphate metabolite. Cytarabine uses hENT1 and dCK for its activation. We hypothesized that cytarabine-resistant leukemia cells retain sensitivity to clofarabine. MATERIALS AND METHODS:Humanmyeloid leukemia HL-60 cells and cytarabine-resistant variant HL/ara-C20 cells were used in the present study. RESULTS: Despite 20-fold cytarabine resistance, the HL/ara-C20 cells exhibited only a 6-fold resistance to clofarabine compared to HL-60 cells. The intracellular concentration of the triphosphate metabolite of cytarabine was reduced to 1/10, and that of clofarabine was halved in the HL/ara-C20 cells. hENT1 and dCK were reduced, but hCNT3 and dGK were not altered in the HL/ara-C20 cells, which might contribute to their retained capability to produce intracellular triphosphate metabolite of clofarabine. CONCLUSION:Clofarabine was cytotoxic to leukemia cells that were resistant to cytarabine.
Entities:
Keywords:
Clofarabine; acute myeloid leukemia; clofarabine triphosphate; cytarabine; drug resistance
Authors: Mikael Crona; Paula Codó; Venkateswara Rao Jonna; Anders Hofer; Aristi P Fernandes; Fredrik Tholander Journal: Mol Oncol Date: 2016-07-26 Impact factor: 6.603
Authors: Michele B Daly; Megan E Roth; Laurent Bonnac; José O Maldonado; Jiashu Xie; Christine L Clouser; Steven E Patterson; Baek Kim; Louis M Mansky Journal: Retrovirology Date: 2016-03-24 Impact factor: 4.602