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

Important note: Information in this article was accurate in 1988. The state of the art may have changed since the publication date.

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

J Biol Chem. 1988 Sep 5;263(25):12391-6. Unique Identifier : AIDSLINE MED/88315031
Ullman B; Coons T; Rockwell S; McCartan K; Department of Biochemistry, Oregon Health Sciences University,; Portland 97201.

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 microM 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 microM. 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 inhibitors 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.

Keywords: Acquired Immunodeficiency Syndrome/DRUG THERAPY Biological Transport Cell Division/DRUG EFFECTS Cell Survival/DRUG EFFECTS Deoxycytidine/*ANALOGS & DERIVATIVES/METABOLISM/PHARMACOLOGY Deoxycytidine Kinase/*GENETICS/METABOLISM Dipyridamole/PHARMACOLOGY Human Kinetics Leukemia, Lymphocytic Mutation Nucleosides/*METABOLISM Phosphorylation Phosphotransferases/*GENETICS Support, U.S. Gov't, P.H.S. T-Lymphocytes/*METABOLISM Thioinosine/ANALOGS & DERIVATIVES/PHARMACOLOGY Tumor Cells, Cultured JOURNAL ARTICLE

881230
M88C0120

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