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

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

Research output: Contribution to journalArticle

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)201-219
Number of pages19
JournalSomatic Cell Genetics
Volume4
Issue number2
DOIs
StatePublished - Mar 1 1978

ASJC Scopus subject areas

  • Genetics

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