Dideoxycytidine metabolism in wild type and mutant CEM cells deficient in nucleoside transport or deoxycytidine kinase.
The growth inhibitory effects and metabolism of 2',3'-dideoxycytidine (ddC) 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 ddC at a concentration of 4 uM inhibited growth of the wild type CEM parental strain by 50%, two nucleoside transport-deficient clones were four-fold resistant to the pyrimidine analog. The deoxycytidine kinase-deficient cell line was virtually completely resistant to growth inhibition by the dideoxynucleoside (ddN) at a concentration or 1024 uM. An 80% diminished rate of [3H]ddC influx into the two nucleoside transport-deficient lines could account for their resistance to the ddN, while the resistance of the deoxycytidine kinase deficient cells to ddC toxicity could be explained by a virtually complete failure to incorporate [3H]ddC 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 ddC toxicity and incorporation. These data indicate that the intracellular metabolism of ddC in CEM cells is initiated by the nucleoside transport system and the cellular deoxycytidine kinase activity.
Ullman
B
B
Department of Biochemistry, Oregon Health Sciences University, Portland 97201.
D000818:Animals; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003842:Deoxycytidine Kinase / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009705:Nucleosides / Q000378:metabolism*; D010770:Phosphotransferases / Q000172:deficiency*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D016047:Zalcitabine / Q000378:metabolism* / Q000494:pharmacology
D009705:Nucleosides; D016047:Zalcitabine; D010770:Phosphotransferases; D003842:Deoxycytidine Kinase