Differential metabolism of 9-beta-D-arabinofuranosylguanine in human leukemic cells.
9-beta-D-Arabinofuranosylguanine (araG) is a nucleoside analogue that elicits cytotoxicity through the intracellular accumulation of its 5'-triphosphate, araGTP, araG is selectively toxic to cultured T-lymphoblasts due to their ability to accumulate higher levels of the cytotoxic metabolite, araGTP, relative to B- and null lymphoblastoid cells. In an effort to determine whether this selectivity may occur in leukemic cells in vivo, we have investigated the metabolism of araG in MOLT-4 T-lymphoblasts. MGL-8 B-lymphoblasts, HL-60 promyelocytes, and HUT-102 mature T-cells and compared it to that in freshly isolated leukemic cells from patients. MOLT-4 T-lymphoblasts were 50- to 380-fold more sensitive to growth inhibition with araG and accumulated 80-fold higher levels of araGTP than any of the other cell lines studied. Incubation of peripheral blood from patients with leukemia with araG for 4 h demonstrated that T-acute lymphocytic leukemia cells accumulated significantly higher median levels of araGTP than did acute myelogenous leukemia or chronic lymphocytic leukemia cells (187 versus 72 and 31 pmol of araGTP per 10(7) cells, respectively), araGTP accumulation was not dependent on the rate of degradation of araG during the incubation. In contrast, araG did not exhibit similar selective growth inhibition, nor did the accumulation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in the freshly isolated leukemic cells differ significantly among T-acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and non-T-, non-B-cell acute lymphocytic leukemia cells. These results demonstrate that the selective metabolism of araG observed in cultured cell lines was representative of the metabolism in freshly isolated leukemic cells. Furthermore, degradation of araG did not limit the accumulation of araGTP in the leukemic cells. These results indicate that araG may be valuable as a selectively acting chemotherapeutic agent in T-lymphoblastic malignancies.
Shewach
D S
DS
Department of Pharmacology, University of Michigan Medical Center, Ann Arbor 48109.
Mitchell
B S
BS
D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001087:Arabinonucleosides / Q000378:metabolism* / Q000494:pharmacology; D001088:Arabinonucleotides / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D006147:Guanine; D006801:Humans; D066298:In Vitro Techniques; D007938:Leukemia / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D014407:Tumor Cells, Cultured
D001087:Arabinonucleosides; D001088:Arabinonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; C028771:9-arabinofuranosylguanine; D006147:Guanine