Summary. 2‐chlorodeoxyadenosine (2‐CdA) and arabinosylcytosine (araC) are nucleoside drugs that are used to treat various leukaemias, although 2‐CdA has not been tested extensively in children with acute lymphoblastic leukaemia (ALL). Nucleoside cytotoxicity depends on the conversion of these agents to 5′‐phosphate derivatives, following drug entry into cells via nucleoside transport (NT) processes. This study compared es nucleoside transporter content, determined using a flow cytometric assay with SAENTA [5′‐S‐(2‐aminoethyl)‐N6‐(4‐nitrobenzyl)‐5′‐thioadenosine] fluorescein, and cytotoxicities of 2‐CdA and araC in fresh lymphoblasts from previously untreated paediatric ALL patients and the human T‐lymphoblast cell line, CCRF‐CEM. Lymphoblast samples from individual patients ranged widely in sensitivity to both 2‐CdA (IC50, 6 nmol/l to > 5 μmol/l; mean = 418 nmol/l; n = 8) and araC (IC50, 59 nmol/l to > 5 μmol/l; mean = 1050 nmol/l; n = 7), although IC50 values for the two drugs were correlated (r = 0·78, P = 0·032, n = 7). Cellular es nucleoside transporter content varied more than 35‐fold among samples from 10 patients. The correlation between es nucleoside transporter content and drug sensitivity was statistically significant for araC (r = −0·93, P = 0·023, n = 5), but not for 2‐CdA (r = −0·57, P = 0·23, n = 6). Exposure of CCRF‐CEM cells to araC resulted in a substantial araC concentration‐dependent increase in the relative survival of es transporter‐deficient cells, whereas the increase was slight following exposure to 2‐CdA. We conclude that, in ALL lymphoblasts, es nucleoside transporter content is a determinant of araC sensitivity and that a deficiency in NT may impart resistance to araC.
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