Dual mechanisms of 9-beta-D-arabinofuranosylguanine resistance in CEM T-lymphoblast leukemia cells

The guanine nucleoside analog araG is selectively toxic to T-lymphoblasts a nd has recently shown promise in treatment of lymphoid malignancies of T-ce ll origin. The molecular mechanism of this tissue-selective cytotoxicity is , however, yet unclear. AraG is phosphorylated, and thereby pharmacological ly activated, by the mitochondrial deoxguanosine kinase and the cytosolic/n uclear deoxycytidine kinase, We have recently shown that araG is predominan tly incorporated into mitochondrial DNA of cancer cell lines, which suggest s a role of mitochondria as its pharmacological target. In the present stud y, we have generated araG-resistant CEM T-lymphoblast cell lines and show t hat araG resistance may occur by two separate molecular mechanisms that can occur sequentially. The first mechanism is associated with a decrease of a raG incorporation into mitochondrial DNA, and the second event is associate d with loss of dCK activity. (C) 2001 Academic Press.