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  • Title: Dual mechanisms of 9-beta-D-arabinofuranosylguanine resistance in CEM T-lymphoblast leukemia cells.
    Author: Curbo S, Zhu C, Johansson M, Balzarini J, Karlsson A.
    Journal: Biochem Biophys Res Commun; 2001 Jul 06; 285(1):40-5. PubMed ID: 11437369.
    Abstract:
    The guanine nucleoside analog araG is selectively toxic to T-lymphoblasts and has recently shown promise in treatment of lymphoid malignancies of T-cell origin. The molecular mechanism of this tissue-selective cytotoxicity is, however, yet unclear. AraG is phosphorylated, and thereby pharmacologically activated, by the mitochondrial deoxguanosine kinase and the cytosolic/nuclear deoxycytidine kinase. We have recently shown that araG is predominantly incorporated into mitochondrial DNA of cancer cell lines, which suggests a role of mitochondria as its pharmacological target. In the present study, we have generated araG-resistant CEM T-lymphoblast cell lines and show that araG resistance may occur by two separate molecular mechanisms that can occur sequentially. The first mechanism is associated with a decrease of araG incorporation into mitochondrial DNA, and the second event is associated with loss of dCK activity.
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