Camptothecin cytotoxicity in mammalian cells is associated with the induction of persistent double strand breaks in replicating DNA
Open Access
- 25 June 1991
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 19 (12), 3295-3300
- https://doi.org/10.1093/nar/19.12.3295
Abstract
Camptothecin is a specific topoisomerase I poison and is highly cytotoxlc to eukaryotic cells. In the present study, we show, using a pulse field gel electrophoresls assay, that camptothecin induces DNA double strand breaks (DSBs) specifically in newly replicated DNA. Camptothecin induces these replication associated ONA 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 toxiclty 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.Keywords
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