Interaction of arabinosyl nucleotides in K562 human leukemia cells.
The objective of this investigation was to evaluate the ability of arabinosyl nucleotides to modulate the cellular metabolism of different arabinosyl nucleosides in K562 cells. The maximum rate of accumulation of the respective 5'-triphosphate (TP) was observed in cells incubated with 10 microM arabinosylcytosine (ara-C), 10 microM arabinosylguanine (ara-G), 300 microM arabinosyl-2-fluoroadenine (F-ara-A), and greater than 1000 microM arabinosyladenine (ara-A). Cell extract fractionation studies demonstrated that ara-C and F-ara-A were phosphorylated by dCyd kinase, whereas ara-A was phosphorylated by dCyd kinase and Ado kinase; ara-G phosphorylation was attributed to dGuo kinase. When nucleoside kinase was rate limiting to arabinosyl nucleotide accumulation, cells preloaded with F-ara-ATP showed increased rates of ara-CTP and ara-GTP accumulation, whereas cells preloaded with ara-CTP had decreased rates of F-ara-ATP and ara-GTP accumulation. Preloading cells with ara-GTP had little effect on arabinosyl nucleoside triphosphate accumulation. F-ara-ATP accumulation was inhibited in cells containing all other arabinosyl nucleotides, whereas ara-ATP metabolism was not affected by preincubation with any other nucleoside. Cells incubated with ara-C and ara-G had a general rise in dNTP, whereas F-ara-A incubation was associated with a decrease in cellular dNTP. The differential effects of arabinosyl nucleotides and cellular metabolism of other arabinosyl nucleosides are due to phosphorylation by distinct nucleoside kinases that likely have characteristic sensitivities to cellular dNTP levels.
Gandhi
V
V
Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Plunkett
W
W
D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001087:Arabinonucleosides / Q000378:metabolism* / Q000494:pharmacology; D001088:Arabinonucleotides / Q000378:metabolism; D003561:Cytarabine / Q000378:metabolism* / Q000494:pharmacology; D003854:Deoxyribonucleotides / Q000032:analysis; D004347:Drug Interactions; D006160:Guanosine Triphosphate / Q000378:metabolism / Q000031:analogs & derivatives; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D010766:Phosphorylation; D010770:Phosphotransferases / Q000032:analysis; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives / Q000378:metabolism
D001087:Arabinonucleosides; D001088:Arabinonucleotides; D003854:Deoxyribonucleotides; D003561:Cytarabine; D001084:Vidarabine Phosphate; D001085:Arabinofuranosylcytosine Triphosphate; C000101:ara-ATP; C028771:9-arabinofuranosylguanine; C022206:9-beta-D-arabinofuranosylguanosine 5'-triphosphate; D006160:Guanosine Triphosphate; D010770:Phosphotransferases; C021892:nucleoside phosphotransferase; D014740:Vidarabine; C024352:fludarabine