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 compound exerts a delayed cytotoxicity due to inhibition of mitochondrial DNA (mDNA) synthesis. We have found that long term exposure of U937 human monoblastoid cells to ddC allowed the selection of a drug-resistant cell line (U937-R) with 66% mDNA, normal ddC transport and altered deoxycytidine kinase kinetic properties. In this paper we show that U937-R cells contain an increased number of mitochondria per cell and a reduced copy number of mDNA/mitochondria. Furthermore, the intracellular concentrations of deoxycytidine 5'-triphosphate (dCTP) and 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) are also reduced although with a higher dCTP/ddCTP ratio in U937-R compared to the parental cells. This mechanism of drug resistance, with drug-resistance based on viral mutations, can provide an explanation for drug failure in antiviral therapy.
Magnani
M
M
Istituto di Chimica Biologica G. Fornaini, Università degli Studi, Urbino, Italy.
Gazzanelli
G
G
Brandi
G
G
Casabianca
A
A
Fraternale
A
A
Chiarantini
L
L
Rossi
L
L
D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics*; D003854:Deoxyribonucleotides / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D066298:In Vitro Techniques; D008928:Mitochondria / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D016047:Zalcitabine / Q000494:pharmacology*
D004272:DNA, Mitochondrial; D003854:Deoxyribonucleotides; D009243:NAD; D016047:Zalcitabine