2',3'-DIDEOXYCYTIDINE INDUCED DRUG-RESISTANCE IN HUMAN-CELLS

2',3'-Dideoxycytidine (ddC) is a nucleoside analogue that inhibits HIV -1 replication in vitro and is currently used in AIDS therapy. This co mpound exerts a delayed cytotoxicity due to inhibition of mitochondria l DNA (mDNA) synthesis. We have found that long term exposure of U937 human monoblastoid cells to ddC allowed the selection of a drug-resist ant cell line (U937-R) with 66% mDNA normal ddC transport and altered deoxycytidine kinase kinetic properties. In this paper we show that U9 37-R cells contain an increased number of mitochondria per cell and a reduced copy number of mDNA/mitochondria. Furthermore, the intracellul ar concentrations of deoxycytidine 5'-triphosphate (dCTP) and 2',3'-di deoxycytidine 5'-triphosphate (ddCTP) are also reduced although with a higher dCTP/ddCTP ratio in U937-R compared to the parental cells. Thi s mechanism of drug resistance, with drug-resistance based on viral mu tations, can provide an explanation for drug failure in antiviral ther apy.