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Analysis of adenosine-mediated pyrimidine starvation using cultured wild-type and mutant mouse T-lymphoma cells

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Somatic Cell Genetics

Abstract

Using the S49 T-cell lymphoma system for the study of immunodeficiency diseases, we characterized several variants in purine salvage and transport pathways and studied their responses to the cytotoxic action of adenosine (5–20 μM) in the presence of adenosine deaminase (ADA) inhibitors. Both an adenosine transport deficient mutant and a mutant lacking adenosine (ado) kinase activity are resistant to the cytotoxic effects of adenosine up to 15 μM. Variants lacking hypoxanthine-guanine phosphoribosyl transferase or adenine phosphoribosyltransferase are sensitive to the killing action of adenosine. We monitored the intracellular concentrations of purine and pyrimidine nucleotides, orotate, and PPribose P in mutant and wild-type cells following the addition of adenosine and an ADA inhibitor. We conclude that at low concentrations, adenosine must be phosphorylated to deplete the cell of pyrimidine nucleotides and PPribose P and to promote the accumulation of orotate. These alterations account for one mechanism of adenosine toxicity.

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Authors and Affiliations

  1. Departments of Medicine and Biochemistry and Biophysics, University of California, San Francisco, 94143, San Francisco, California

    Lorraine J. Gudas, Amos Cohen, Buddy Ullman & David W. Martin Jr.

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  1. Lorraine J. Gudas
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  2. Amos Cohen
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  3. Buddy Ullman
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  4. David W. Martin Jr.
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Gudas, L.J., Cohen, A., Ullman, B. et al. Analysis of adenosine-mediated pyrimidine starvation using cultured wild-type and mutant mouse T-lymphoma cells. Somat Cell Mol Genet 4, 201–219 (1978). https://doi.org/10.1007/BF01538985

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  • DOI: https://doi.org/10.1007/BF01538985

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