Furine Deoxynucleoside Toxicity in Nondividing Human Lymphoid Cells

Cultured leukemic T-lymphoblasts, incubated in the pres ence of inhibitors of adenosine deaminase, are exquisitely sensitive to growth inhibition by deoxyadenosine. An analogy between this phenomenon and human combined immunodefi ciency 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 accu mulation of high intracellular concentrations of deoxyadenosine triphosphate (dATP) following phosphorylation of deoxyaden osine, 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 incu bation with jUMconcentrations of deoxyadenosine in the pres ence 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 el evate 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 incu bation with deoxyadenosine. Furthermore, these nondividing peripheral blood lymphocytes were killed by JUMconcentrations 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 aden osine deaminase inhibitors as lympholytic immunosuppressants or as agents cytotoxic to noncycling malignant lymphoid cells.