Metabolism and selectivity of arabinonucleoside in human lymphoid cells.
The selective toxicity of purine deoxynucleosides against lymphoid cells appears to be mediated by a preferential accumulation of the corresponding triphosphates in these cells. We report a study of the metabolism and toxicity of arabinonucleosides of guanine and cytosine toward human T- and B-lymphoblastoid-cell lines. Both compounds inhibited the growth of T lymphoblasts at concentrations less than 2 microM. However, only ara-G exhibited a strong selectivity for T lymphocytes as indicated by a 100-fold greater toxicity to T than B cells. ara-G is not significantly degraded to guanine but is metabolized to the triphosphate. In common with the other arabinonucleoside, cytotoxicity by ara-G was associated with specific inhibition of DNA synthesis in cells. The capacity of T cells (CCRF-CEM) to accumulate ara-GTP was dependent primarily on deoxycytidine kinase. The level of intracellular ara-GTP accumulated after incubation with the corresponding nucleoside was 20- to 40-fold higher in T cells than either of two B-lymphoblast-cell lines, WI-L2 or PF-2S. The levels of phosphorylating activity for ara-C in extracts of T- and B-cell lines were approximately equal; in contrast, ara-G phosphorylating activity was four- to fivefold higher in B lymphoblasts. After removal of arabinonucleosides from the culture medium, ara-GTP levels in B lymphoblasts declined at a rate that was two to four times faster than that of ara-CTP. In marked contrast, no catabolism of the arabinonucleoside triphosphates was detected in T lymphoblasts. These results suggest that the selectivity of arabinonucleosides to human lymphoid cells of various phenotypes can be correlated with their nucleotide metabolism. The selectivity of ara-G for T and B cells can be correlated with their differential ability to catabolize ara-GTP.
Fridland
A
A
Verhoef
V
V
D001087:Arabinonucleosides / Q000378:metabolism* / Q000633:toxicity; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003561:Cytarabine / Q000378:metabolism* / Q000633:toxicity; D003842:Deoxycytidine Kinase / Q000378:metabolism; D006801:Humans; D010770:Phosphotransferases / Q000378:metabolism; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
D001087:Arabinonucleosides; D003561:Cytarabine; C028771:9-arabinofuranosylguanine; D010770:Phosphotransferases; D003842:Deoxycytidine Kinase; C021892:nucleoside phosphotransferase