Metabolic basis of arabinonucleoside selectivity for human leukemic T- and B-lymphoblasts.
Purine analogues are potentially useful agents for selective chemotherapy of lymphoproliferative diseases. We compared the toxic effects of various arabinonucleosides against eight human T- and B-lymphoblastoid lines. The arabinosides of cytosine (ara-C), 2-fluoroadenine (F-ara-A), adenine (ara-A) and guanine (ara-G) all inhibited the growth of T-lymphoblasts at concentrations below 2 microM. Only ara-G showed strong selectivity for T-cells, as indicated by a 15- to 250-fold greater toxicity toward T-cell lines than B-cell lines. To investigate the biochemical basis for ara-G selectivity, we compared the metabolism of the arabinonucleosides in CCRF-CEM (T-) versus PF-2S (B-) lymphoblasts. Comparison of arabinonucleoside triphosphate accumulation indicated differences favoring selective ara-GTP formation in T-cells. In contrast, ara-C, ara-A, and F-ara-A formed almost corresponding amounts of their triphosphates in both cell types. Triphosphate accumulation correlated directly with inhibition of DNA synthesis in CCRF-CEM and PF-2S cells. PF-2S cells accumulated less than 20% ara-GTP from the nucleoside than did CCRF-CEM cells. Nucleoside kinase measurements showed no significant differences in arabinonucleoside phosphorylation that could account for the preferential ara-GTP accumulation in T-cells. After removal of arabinonucleoside-containing medium, ara-GTP levels in PF-2S cells declined with a half-life of 49 min whereas, in CCRF-CEM cells, the level of analogue triphosphate remained unchanged. Furthermore, the half-life of ara-CTP, ara-ATP, and F-ara-ATP in the B-cells was 3- to 5-fold longer than that of ara-GTP. These results indicate that ara-G is more selective than other known arabinonucleosides; such selectivity warrants further assessment of the therapeutic potential of this agent against T-cell malignancies and other lymphoid disorders.
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Verhoef
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Fridland
D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D001087:Arabinonucleosides / Q000378:metabolism / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D003849:Deoxyguanosine / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014740:Vidarabine / Q000494:pharmacology; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D001087:Arabinonucleosides; D003561:Cytarabine; D001084:Vidarabine Phosphate; D001085:Arabinofuranosylcytosine Triphosphate; C000101:ara-ATP; C028771:9-arabinofuranosylguanine; D014740:Vidarabine; D003849:Deoxyguanosine