Abstract
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.
Highlights
Delayed Cytotoxicity and Selective Loss of Mitochondrial DNA in Cells Treated with the Anti-human Immunodeficiency VirusCompound 2’,3’-Dideoxycytidine”
Mitocontent of mitochondrial DNA was found to decrease chondrial defects have been related to peripheral neuropathy and the rate of glycolysis was found to increase with [9].These observations suggest that mitochondria may bethe continuousexposure of cells to ddC
The reduction in cellular content of is characterized by a delayed arrest of cell growth, we mitochondrial DNA caused by ddC may partially ex- investigated whether ddC induces delayed cytotoxicity and plain the delayed toxicity observed in acquired immu- affects mitochondria in Molt-4F cells, a human T lymphonodeficiency syndrome patients treated with the drug. blastic cell line
Summary
0 1989 by The American Society for Biochemistry and Molecular Biology, Inc. Vol 264, No 20, Issue of July 15, pp. 11934-11937,1989 Printed in U.S.A. The reduction in cellular content of is characterized by a delayed arrest of cell growth (lo), we mitochondrial DNA caused by ddC may partially ex- investigated whether ddC induces delayed cytotoxicity and plain the delayed toxicity observed in acquired immu- affects mitochondria in Molt-4F cells, a human T lymphonodeficiency syndrome patients treated with the drug. The lactic acid content of the did not increase from day 2 to day 14 of ddC treatment (Fig. 1).the delayed cytotoxicity in Molt-4F cells after exposure to ddC did not result from continued accumulation of ddCTP in thecells. A dose-dependent increase in the concentration of lactate in the culture medium after 3 days of exposure to ddC (Fig. 2) This result clearly indicates that glycolysis wasstimulated in the ddC-treated cells and suggests that mitochondrial function was affected by ddC. The topoisomerase I gene waschosen as a controflor the amountof genomic DNA
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