Purine deoxynucleoside toxicity in nondividing human lymphoid cells

Richard F. Kefford*, Richard M. Fox

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Cultured leukemic T-lymphoblasts, incubated in the presence of inhibitors of adenosine deaminase, are exquisitely sensitive to growth inhibition by deoxyadenosine. An analogy between this phenomenon and human combined immunodeficiency disease associated with inborn adenosine deaminase deficiency and the use of inhibitors of adenosine deaminase in the management of T-cell acute lymphoblastic leukemia has been noted. These phenomena are believed to reflect accumulation of high intracellular concentrations of deoxyadenosine triphosphate (dATP) following phosphorylation of deoxyadenosine, inhibiting replicating T-cells. In an attempt to extend these observations to noncultured, nonleukemic T-cells, we studied deoxyadenosine metabolism in human thymocytes. Human thymuses were separated into large replicating and small nondividing cell types by centrifugal elutriation. Both thymocyte subpopulations elevated their dATP pools on incubation with μm concentrations of deoxyadenosine in the presence of erythro-9-[3-(2-hydroxynonyl)]adenosine an inhibitor of adenosine deaminase. These dATP pool rises were similar in extent to those found in cultured leukemic T-lymphoblasts. However, the finding that small nonreplicating thymocytes elevate their dATP pool was unexpected. This prompted study of unstimulated peripheral blood lymphocytes. These cells (T and non-T) showed a similar elevation of their dATP pool on incubation with deoxyadenosine. Furthermore, these nondividing peripheral blood lymphocytes were killed by μm concentrations of deoxyadenosine in the presence of an inhibitor of adenosine deaminase. The biochemical mechanism of this Go-phase cell death is not known. These findings provide impetus for the investigation of adenosine deaminase inhibitors as lympholytic immunosuppressants or as agents cytotoxic to noncycling malignant lymphoid cells.

Original languageEnglish
Pages (from-to)324-329
Number of pages6
JournalCancer Research
Volume42
Issue number1
Publication statusPublished - 1 Jan 1982
Externally publishedYes

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