Document 0284
 DOCN  M95B0284
 TI    2',3'-Dideoxycytidine induced drug resistance in human cells.
 DT    9511
 AU    Magnani M; Gazzanelli G; Brandi G; Casabianca A; Fraternale A;
       Chiarantini L; Rossi L; Istituto di Chimica Biologica G. Fornaini,
       Universita degli; Studi, Urbino, Italy.
 SO    Life Sci. 1995 Jul 21;57(9):881-7. Unique Identifier : AIDSLINE
       MED/95356702
 AB    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.
 DE    Cell Line  Deoxyribonucleotides/METABOLISM  Drug Resistance  DNA
       Replication/DRUG EFFECTS  DNA, Mitochondrial/*GENETICS  Human  In Vitro
       Mitochondria/DRUG EFFECTS  NAD/METABOLISM  Support, Non-U.S. Gov't
       Zalcitabine/*PHARMACOLOGY  JOURNAL ARTICLE

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