Abstract
AraG is a deoxyguanosine (dGuo) analog which exhibits selective cytotoxicity for T relative to B lymphoblasts. This drug is metabolized intracellularly to the 5'-triphosphate, araGTP, which is associated with the inhibition of DNA synthesis. In order to investigate the enzymes responsible for the selective araG metabolism, we have isolated an araG-resistant clonal cell line (designated line 24B3) from MOLT-4 T lymphoblasts which exhibits a 600-fold and 36-fold increase in IC50 values for araG and dGuo, respectively. In contrast, this cell line is only 3- to 4-fold less sensitive to arabinosylcytosine (araC) relative to unselected MOLT-4 cells. Following a 4 hr incubation with araG, dGuo and araC, the intracellular accumulation of the active metabolites araGTP and dGTP is decreased 8- and 9-fold, respectively, compared to only a 3-fold reduction in araCTP accumulation in the resistant cells. Similar decreases in nucleotide accumulation are observed in cell-free lysates of the 24B3 cell line. The degradation of araG is the same in both sensitive and resistant cell lines. In addition, the HL-60 promyelocytic leukemia cell line is 300-fold less sensitive to araG than are T lymphoblasts, and the ability of the promyelocytes to accumulate araGTP is similar to that of the 24B3 cell line. These data suggest that sensitivity to araG is mediated through a cell-specific kinase which is more selective for dGuo analogs than for a deoxycytidine analog such as araC.
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Shewach, D., Mitchell, B. CHARACTERIZATION OF ARABINOSYLGUANINE (AraG) RESISTANCE IN A LYMPHOBLASTOID CELL LINE: 188. Pediatr Res 19, 775 (1985). https://doi.org/10.1203/00006450-198507000-00208
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DOI: https://doi.org/10.1203/00006450-198507000-00208
