Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2',3'-dideoxycytidine.
The compound 2',3'-dideoxycytidine (ddC) is a potent inhibitor of human immunodeficiency virus replication in vitro and is currently in clinical trials for treatment of acquired immunodeficiency syndrome. The compound was found to exert delayed cytotoxicity against Molt-4F cells, a human T lymphoblastic cell line. At a concentration as low as 0.1 microM, the doubling time of the cells was increased after 8 days of ddC treatment. This concentration is 5-fold lower than plasma levels reached in clinical trials. The cells finally died after a 2-week exposure to 0.1 or 0.2 microM ddC. The delayed cytotoxicity was not due to a greater accumulation of 2',3'-dideoxycytidine triphosphate in cells with longer exposure to the compound. The cellular content of mitochondrial DNA was found to decrease and the rate of glycolysis was found to increase with continuous exposure of cells to ddC. The mitochondrial toxicity and cell growth inhibition were reversed when ddC was removed. The reduction in cellular content of mitochondrial DNA caused by ddC may partially explain the delayed toxicity observed in acquired immunodeficiency syndrome patients treated with the drug.
Chen
C H
CH
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill 27599-7365.
Cheng
Y C
YC
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000187:drug effects*; D015245:Deoxyribonuclease BamHI; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004587:Electrophoresis, Agar Gel; D006678:HIV / Q000187:drug effects*; D007773:Lactates / Q000032:analysis; D019344:Lactic Acid; D016047:Zalcitabine / Q000031:analogs & derivatives*
D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D015224:Dideoxynucleosides; D007773:Lactates; D019344:Lactic Acid; D016047:Zalcitabine; C050624:2',3'-dideoxycytidinene; D015245:Deoxyribonuclease BamHI