Cellular pharmacology of 1-beta-D-arabinofuranosylcytosine in human myeloid, B-lymphoid and T-lymphoid leukemic cells.
The in vitro inhibitory action and metabolism of 1-beta-D-arabinofuranosylcytosine (ara-C) on human myeloid (HL-60), B-lymphoid (RPMI-8392), and T-lymphoid (Molt-3) leukemic cells was compared. Ara-C produced greater inhibitory effects in Molt-3 cells than in either HL-60 or RPMI-8392 cells. At a 48 h exposure, ara-C was 7 and 10 times more cytotoxic to Molt-3 cells than to HL-60 and RPMI-8392 cells, respectively. The total ara-C uptake to nucleotides and the formation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) was about 5 times greater in Molt-3 cells than in either HL-60 or RPMI-8392 cells. The incorporation of ara-C into DNA was also higher in Molt-3 cells than in either HL-60 or RPMI-8392 cells. The mean intracellular half-life of ara-CTP was 31.7, 59.4, and 155 min for RPMI-8392, HL-60, and Molt-3 leukemic cells, respectively. The Km and Vmax values of ara-C for deoxycytidine kinase and the feedback inhibition of this enzyme by ara-CTP in the different leukemic cell lines could not explain the differences in metabolism of this analogue in these cells. These data indicate the increased sensitivity of T-lymphoid leukemic cells to ara-C than as compared with B-lymphoid and myeloid leukemic cells was due to an increased rate of formation and a longer half-life of ara-CTP in the T-cells.
Momparler
R L
RL
Department de pharmacologie, Université de Montréal, Quebec, Canada.
Onetto-Pothier
N
N
Bouffard
D Y
DY
Momparler
L F
LF
D001085:Arabinofuranosylcytosine Triphosphate / Q000032:analysis; D002460:Cell Line; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000378:metabolism; D006801:Humans; D015448:Leukemia, B-Cell / Q000378:metabolism*; D007945:Leukemia, Lymphoid / Q000201:enzymology / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000378:metabolism*; D015458:Leukemia, T-Cell / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects
D004273:DNA, Neoplasm; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D003842:Deoxycytidine Kinase