EFFECTS OF CYTOSINE-ARABINOSIDE ON HUMAN LEUKEMIA-CELLS

Cytosine arabinoside (Ara-C) is used to treat leukemias, with complete remission induced by combination chemotherapy in approximately 70% of cases of acute myelogenous leukemia (AML). Ara-CTP acts as a competit ive inhibitor of DNA polymerase and may also be incorporated into DNA. Accumulation of deoxyribonucleoside triphosphates (dNTPs) induced by Ara-C may indicate disruption of DNA synthesis in susceptible leukemia cells. A procedure has been developed for the quantification of Ara-C TP and dNTPs from small samples of leukaemia cells from patients (4 x 10(7) cells) activated with concanavalin A (10 mu g/ml, 48 hr) and gro wn in the presence of [P-32]orthophosphate (1.1 mu M, 9 x 10(6) Ci/mol , 16 hr). The susceptibilities to Ara-C of the human leukemia cell lin es CCRF-CEM (IC50 = 6.30 nM), CCRF-HSB-2 (IC50 = 10.4 nM) and MOLT-4 ( IC50 = 10.0 nM) may be correlated with their abilities to accumulate h igh concentrations of Ara-CTP ( > 1000 amol/cell) with increases of be tween 1.3- and 3.4-fold in dATP, dGTP and dTTP for the four cell lines , while dCTP decreased between 0.23- and 0.78-fold. By contrast, an Ar a-C-resistant derivative of HL-60 cells (IC50 = 400 nM) accumulated on ly low concentrations of Ara-CTP (71 amol/cell) without significant ch anges in dNTPs. High concentrations of Ara-CTP in leukemia cells induc e accumulations of dATP, dGTP and dTTP due to inhibition of DNA synthe sis, and depletion of dCTP. This imbalance in the pools of the four dN TPs could lead to genetic miscoding and cell death. Copyright (C) 1996 Elsevier Science Ltd