Differential Sensitivity of Human Leukemic T Cell Lines and B Cell Lines to Growth Inhibition by Deoxyadenosine

Open Access
Publisher Website
Google Scholar
Abstract
Previous experiments have suggested that the lymphospecific toxicity associated with inherited deficiencies of the enzymes adenosine deaminase (ADA) (adenosine aminohydrolase; EC 3.5.4.4) and purine nucleoside phosphorylase (PNP) (purine-nucleoside orthophosphate ribosyltransferase; EC 2.4.2.1) is mediated by toxic purine deoxyribonucleotides, which are selectively trapped in lymphoid tissues enriched in purine deoxyribonucleoside kinase. This hypothesis, however, does not fully explain the greater impairment of T as opposed to B cell functions seen in ADA and particularly PNP deficiency. In the present experiments we have compared the inhibitory effects of deoxyadenosine and adenosine, the natural substrates of ADA, on three leukemic T cell lines and three B cell lines in long-term tissue culture. The leukemic T cell lines were 20-fold more sensitive than the B cell lines to the toxic effects of deoxyadenosine, but not adenosine. In the presence of the ADA inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, 2.6 µM deoxyadenosine inhibited leukemic T cell growth by 50%. The increased sensitivity of the T cell lines to deoxyadenosine was associated with the accumulation of intracellular deoxyadenosine triphosphate (deoxyATP), and with inhibition of DNA but not RNA synthesis. In both the T and B cell lines, deoxyadenosine toxicity could be reversed by the addition of deoxycytidine to the culture medium. Among other toxic compounds tested, the leukemic T cells were several-fold more sensitive than the B cells to thymidine, a known ribonucleotide reductase inhibitor. Thus leukemic T cells in vitro appear to be very susceptible to the toxic effects of ribonucleotide reductase inhibitors. Purine deoxyribonucleoside analogs that are not substrates for adenosine deaminase or purine nucleoside phosphorylase, and thymidine analogs that are not substrates for thymidine phosphorylase, may have potential value as T cell-selective chemotherapeutic agents.