Resistance to 9-β-D-arabinofuranosyl-2-fluoroadenine due to reduced incorporation into DNA from competition by excess deoxyadenosine triphosphate : Implications for different sensitivities to nucleoside analogues

• Published in: International journal of hematology Vol. 81; no. 5; pp. 405 - 412
• Main Authors: YOSHIO, Nobuyuki, KAWAI, Yasukazu, HORI, Hiroki, UEDA, Takanori
• Format: Journal Article
• Language: English
• Published: Tokyo Springer 01.06.2005
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Biotransformation; Cell Line, Tumor; Cell Proliferation - drug effects; Cytarabine - pharmacokinetics; Deoxyadenine Nucleotides - analysis; Deoxyadenine Nucleotides - metabolism; Deoxycytosine Nucleotides - analysis; DNA - metabolism; Drug Interactions; Drug Resistance, Neoplasm; Hematologic and hematopoietic diseases; Hydroxyurea - pharmacology; Medical sciences; Mice; Nucleosides - pharmacology; Nucleosides - therapeutic use; Vidarabine - analogs & derivatives; Vidarabine - pharmacokinetics; Competition; Incorporation; Hematology; Enzyme; Transferases; 9-p-D-Arabinofuranosyl-2-fluoroadenine; Cross-resistance; Rodentia; Malignant hemopathy; L1210-Leukemia; Deoxyadenosine; dATP pool; Vertebrata; Deoxycytidine kinase; Sensitivity; Mammalia; Mouse; Analog; DNA; Established cell line; Nucleoside; L1210 leukemia cells; Cross resistance
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1532/IJH97.05008

The cytotoxic action of the deoxyadenosine analogue 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) depends on the incorporation into DNA after being phosphorylated to F-ara-A triphosphate (F-ara-ATP) by deoxycytidine kinase (dCK). The mechanisms of resistance to F-ara-A were investigated in a newly established variant of L1210 mouse leukemia cells (L1210/F). L1210/F was more than 41-fold more resistant to F-ara-A than the parental cell line and had a 55% lower dCK activity. Interestingly, L1210/F showed a modest level of cross-resistance to deoxycytidine analogues phosphorylated by dCK, for instance, 1-beta-D-arabinofuranosylcytosine (ara-C). The comparative study of F-ara-A and ara-C demonstrated that the difference in the accumulation of their respective triphosphates was minor. In contrast, the incorporation of F-ara-A into DNA was strikingly suppressed compared with that of ara-C. In general, the high natural triphosphate levels interfere with corresponding analogue incorporation into DNA. The deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate pool sizes in L1210/F cells were increased by 4.9-fold and 1.9-fold, respectively, compared with the parental cells. Treatment with hydroxyurea increased the ratio of F-ara-ATP to dATP 2.1-fold and enhanced the action of F-ara-A in L1210/F. This is the first cell line to show that the profoundly defective incorporation of F-ara-A into DNA during competition with excess dATP confers a high degree of resistance to F-ara-A.