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%.