Genetic analysis of 2',3'-dideoxycytidine incorporation into cultured human T lymphoblasts

B. Ullman, T. Coons, S. Rockwell, K. McCartan

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58 Scopus citations

Abstract

In order to analyze the cellular determinants that mediate the action of 2'-3'-dideoxycytidine, the growth inhibitory and cytotoxic effects and the metabolism of the dideoxynucleoside were examined in wild type human CEM T lymphoblasts and in mutant populations of CEM cells that were genetically deficient in either nucleoside transport or deoxycytidine kinase activity. Whereas 2',3'-dideoxycytidine at a concentration of 5 μM inhibited growth of the wild type CEM parental strain by 50%, two nucleoside transport-deficient clones were 4-fold resistant to the pyrimidine analog. The deoxycytidine kinase-deficient cell line was virtually completely resistant to growth inhibition by the dideoxynucleoside at a concentration of 1024 μM. An 80% diminished rate of 2',3'-[5,6-3H]dideoxycytidine influx into the two nucleoside transport-deficient lines could account for their resistance to the dideoxynucleoside, while the resistance of the deoxycytidine kinase-deficient cells to 2',3'-dideoxycytidine toxicity could be explained by a virtually complete failure to incorporate 2',3'-[5,6-3H]dideoxycytidine in situ. Two potent inhibitor of mammalian nucleoside transport, 4-nitrobenzylthioinosine and dipyridamole, mimicked the effects of a genetic deficiency in nucleoside transport with respect to 2',3'-dideoxycytidine toxicity and incorporation. These data indicate that the intracellular metabolism of 2',3'-dideoxycytidine in CEM cells is initiated by the nucleoside transport system and the cellular deoxycytidine kinase activity.

Original languageEnglish (US)
Pages (from-to)12391-12396
Number of pages6
JournalJournal of Biological Chemistry
Volume263
Issue number25
StatePublished - Dec 1 1988

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Ullman, B., Coons, T., Rockwell, S., & McCartan, K. (1988). Genetic analysis of 2',3'-dideoxycytidine incorporation into cultured human T lymphoblasts. Journal of Biological Chemistry, 263(25), 12391-12396.