Cell cycle-specific metabolism of arabinosyl nucleosides in K562 human leukemia cells.
Exponentially growing K562 cells incubated with 1-beta-D-arabinofuranosylcytosine (ara-C) accumulate ara-C triphosphate (ara-CTP) at a higher rate and to a greater concentration after pretreatment with 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) than do cells treated with ara-C alone. Potentiation of ara-C metabolism is due in part to an indirect effect of F-ara-A triphosphate (F-ara-ATP)-mediated reduction in deoxynucleotide pools and consequent activation of deoxycytidine kinase. Because the levels of deoxynucleotide pools and the activity of deoxycytidine kinase are cell cycle-specific, we investigated the effect of cell cycle phases on the accumulation of ara-CTP and the influence of F-ara-A pretreatment on such accumulation. Exponentially growing K562 cells were fractionated into G1, S, and G2+M phase-enriched subpopulations (each enriched by > 60%) by centrifugal elutriation. The rate of ara-CTP accumulation was 22, 25, and 14 microM/h and the rate of F-ara-ATP accumulation was 38, 47, and 33 microM/h in the G1, S, and G2+M subpopulations, respectively. The rate of elimination of arabinosyl triphosphates was similar among the different phases of the cell cycle. After pretreatment with F-ara-A, the rate of ara-CTP accumulation in the G1, S, and G2+M phase-enriched subpopulations was 43, 37, and 26 microM/h, indicating a 1.7-, 1.5-, and 1.9-fold increase, respectively. These results suggest that a combination of F-ara-A and ara-C may effectively potentiate ara-CTP accumulation in all phases of the cell cycle. This observation is consistent with the results of studies on the modulation of ara-C metabolism by F-ara-A in lymphocytes and leukemia blasts obtained from patients with chronic lymphocytic leukemia and acute myelogenous leukemia, respectively.
Gandhi
V
V
Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Plunkett
W
W
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism / Q000493:pharmacokinetics; D001088:Arabinonucleotides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D002453:Cell Cycle / Q000502:physiology; D003561:Cytarabine / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004357:Drug Synergism; D016193:G1 Phase / Q000502:physiology; D016195:G2 Phase / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008677:Metaphase / Q000502:physiology; D009711:Nucleotides / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; D001088:Arabinonucleotides; D009711:Nucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; C034957:2-fluoro-araATP; D003842:Deoxycytidine Kinase; D014740:Vidarabine; C024352:fludarabine