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 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.
Curbo
S
S
Division of Clinical Virology F-68, Huddinge University Hospital, Stockholm, S-141 86, Sweden.
Zhu
C
C
Johansson
M
M
Balzarini
J
J
Karlsson
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D004273:DNA, Neoplasm; C028771:9-arabinofuranosylguanine