Molecular basis of 2',3'-dideoxycytidine-induced drug resistance in human cells

Human monoblastoid cells (U937) grown in the presence of therapeutically relevant dideoxycytidine concentrations (0.1 microM) become resistant to the drug thanks to an altered deoxycytidine kinase. In this paper we show that deoxycytidine kinase mRNA is significantly reduced in drug-resistant U937 cells (U937-R) although the deoxycytidine kinase promoter is normal. Anumber of nucleotide deletions, insertions and substitutions was found in the coding region of deoxycytidine kinase gene. Several identified mutations result in truncated forms of the enzyme or in the introduction of stop codons: in one case a complete lack of exon 4 was found. Thus, the deoxycytidine kinase gene accumulates mutations at a very high rate, as already reported for other cytidine analogues (i.e. Ara C) suggesting that the design of new antiviral or anticancer drugs of the cytidine family should take into account the potential development of cell resistance as a critical factor in drug failure.