High degree of resistance to 5-aza-2'-deoxycytidine in L1210 cells in vitro associated with almost complete loss of deoxycytidine kinase activity.
In L1210 mouse leukemic cells the resistance towards 5-aza-2'-deoxycytidine was developed in vitro by stepwise selection in increasing concentrations of this drug. According to the respective IC50 values the variant cell line was at least 7000-fold more resistant to 5-aza-2'-deoxycytidine, 3300-fold to arabinosyl 5-azacytosine and 20,000-fold to arabinosyl cytosine in comparison to the parental cell line. The uptake of radioactivity derived from 5-aza-2'-deoxycytidine in variant cells was depressed by 95% as compared to the parental strain and no uptake occurred in case of 2'-deoxycytidine. The phosphorylation of this natural precursor and of its analog in the presence of the cell-free system derived from the variant cell line was nearly completely abolished. In resistant cells the amount of DNA 5-methyl-cytosine relative to cytosine was decreased by 24-44%.
D044503:5-Methylcytosine; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002460:Cell Line / Q000187:drug effects; D002478:Cells, Cultured; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D000077209:Decitabine; D003841:Deoxycytidine / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D004351:Drug Resistance; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*
D003841:Deoxycytidine; D044503:5-Methylcytosine; D000077209:Decitabine; D003596:Cytosine; D004248:DNA (Cytosine-5-)-Methyltransferases; D010770:Phosphotransferases; D003842:Deoxycytidine Kinase; D001374:Azacitidine