CYTOTOXIC AND METABOLIC EFFECTS OF ADENOSINE AND ADENINE ON HUMAN LYMPHOBLASTS

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  • 1 January 1978
    • journal article
    • research article
    • Vol. 38  (8) , 2357-2362
Abstract
The metabolic and growth inhibitory effects of adenosine toward the human lymphoblast line WI-L2 were potentiated by the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and coformycin. EHNA, 5 .mu.M, or coformycin, 3.5 .mu.M, at concentrations that inhibited adenosine deaminase activity more than 90%, had little effect on cell growth or the metabolic parameters studied. Adenosine, 50.mu.M, plus EHNA, 5 .mu.M, arrested cell growth in parent and adenosine kinase-deficient lymphoblasts, implicating the nucleoside as the mediator of the cytostatic effect. Adenosine, 50 .mu.M, in combination with the adenosine deaminase inhibitors reduced 14CO2 generation from [1-14C]glucose by 38%, depleted 5-phosphoribosyl-1-pyrophosphate by more than 90% and reduced pyrimidine ribonucleotide concentrations. Uridine, 10 or 100 .mu.M, reversed adenosine plus EHNA growth inhibition in WI-L1 but not in adenosine kinase mutants. Adenine, 500 .mu.M, which may be converted to the same intracellular nucleotides as adenosine, reduced the growth rate by 50% in parent and adenine phosphoribosyltransferase-deficient lymphoblasts. Although adenine also depleted cells of 5-phosphoribosyl-1-pyrophosphate and reduced pyrimidine ribonucleotide by 50%, the mechanisms of adenine and adenosine toxicity differ. In contrast to the ability of uridine to reverse adenosine cytostatis, growth inhibition by adenine was not reversed by uridine, indicating that pyrimidine ribonucleotide depletion is not the primary mechanism of adenine toxicity. [These findings have relevance to the use of adenosine deaminase inhibitors in cancer chemotherapy and to the mechanism for the severe combined immunodeficiency occurring in patients with hereditary absence of adenosine deaminase.].