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Camptothecin is a specific topoisomerase I poison and is highly cytotoxic to eukaryotic cells. In the present study, we show, using a pulse field gel electrophoresis assay, that camptothecin induces DNA double strand breaks (DSBs) specifically in newly replicated DNA. Camptothecin induces these replication associated DNA DSBs in a dose-dependent manner. At levels of the drug which are toxic to the cell, these breaks are long-lived, and still measurable 24 hr after treatment. Both camptothecin induced DSBs and cytotoxicity are prevented by co-exposure with aphidicolin--a result which indicates that ongoing DNA synthesis is required for the production of DNA DSBs and cell killing. It has been proposed that camptothecin toxicity involves an interaction between the replication machinery and a drug-mediated topoisomerase I-DNA cleavable complex. The present work indicates, for the first time in mammalian cellular DNA, that one possible outcome of this interaction is a replication-associated DSB, a lesion which is likely to be highly cytotoxic.

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

25/06/1991

Volume

19

Pages

3295 - 3300

Keywords

Antiviral Agents, Aphidicolin, Camptothecin, Cell Division, Cell Line, DNA, DNA Damage, DNA Replication, Diterpenes, Electrophoresis, Agar Gel, Humans