Cytarabine-resistant leukemia cells are moderately sensitive to clofarabine in vitro.

Abstract

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.

• Authors: Takahiro Yamauchi, Kanako Uzui, Rie Nishi, Hiroko Shigemi, Takanori Ueda
• Journal: Anticancer research (Anticancer Res) Vol. 34 Issue 4 Pg. 1657-62 (Apr 2014) ISSN: 1791-7530 [Electronic] Greece
• PMID: 24692694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenine Nucleotides
• Antimetabolites, Antineoplastic
• Arabinonucleosides
• Equilibrative Nucleoside Transporter 1
• Membrane Transport Proteins
• cif nucleoside transporter
• Cytarabine
• Clofarabine
• Phosphotransferases (Alcohol Group Acceptor)
• deoxyguanosine kinase

Topics

• Adenine Nucleotides (metabolism, pharmacology, toxicity)
• Antimetabolites, Antineoplastic (metabolism, pharmacology, toxicity)
• Apoptosis (drug effects)
• Arabinonucleosides (metabolism, pharmacology, toxicity)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Clofarabine
• Cytarabine (pharmacology, toxicity)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Equilibrative Nucleoside Transporter 1 (metabolism)
• HL-60 Cells
• Humans
• Intracellular Space (metabolism)
• Leukemia, Myeloid, Acute (drug therapy, metabolism)
• Membrane Transport Proteins (metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (metabolism)