TY - JOUR
T1 - Interaction of arabinosyl nucleotides in K562 human leukemia cells
AU - Gandhi, Varsha
AU - Plunkett, William
N1 - Funding Information:
* This work was supported by Grant CH-130 from the American Cancer Society and Grant CA28596 from the National Cancer Institute. t Correspondence: William Plunkett, Ph.D., Department of Medical Oncology, Box 52, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. $ Abbreviations: ara-C, ara-CTP, 1-gD-arabinofuranosylcytosine and its 5’-triphosphate; ara-G, ara-GTP, l-P-D-arabinofuranosylguanine and its 5’-triphosphate; ara-A, ara-ATP, 9-P-D-arabinofuranosyladenine and its 5’-triphosphate; F-ara-A, F-ara-ATP, 9-P-D-arabinofuranosyl-2-fluoroadenine and its 5’-triphosphate; ara-N, ara-NTP, an arabinofuranosyl nucleoside and an arabinofuranosyl 5’-triphosphate; and DEAE, diethylaminoethyl.
PY - 1989/10/15
Y1 - 1989/10/15
N2 - 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 μM arabinosylcytosine (ara-C), 10 μM arabinosylguanine (ara-G), 300 μM arabinosyl-2-fluoroadenine (F-ara-A), and > 1000 μM 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 arabinosyl 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.
AB - 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 μM arabinosylcytosine (ara-C), 10 μM arabinosylguanine (ara-G), 300 μM arabinosyl-2-fluoroadenine (F-ara-A), and > 1000 μM 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 arabinosyl 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.
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U2 - 10.1016/0006-2952(89)90127-5
DO - 10.1016/0006-2952(89)90127-5
M3 - Article
C2 - 2479383
AN - SCOPUS:0024421965
SN - 0006-2952
VL - 38
SP - 3551
EP - 3558
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 20
ER -