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Differential Requirement of DNA Replication for the Cytotoxicity of DNA Topoisomerase I and II Inhibitors in Chinese Hamster DC3F Cells

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

The cytotoxicity of topoisomerase inhibitors is thought to result from the induction of enzyme-mediated DNA breaks. The fact that these breaks reverse rapidly in cells programmed to die, led us to investigate further the cytotoxic mechanisms of topoisomerase I (camptothecin) and topoisomerase II inhibitors (VP-16 and amsacrine) in Chinese Hamster lung fibroblasts (DC3F). Exposures (30 min) to camptothecin produced limited cell killing with approximately 20% of the cells naturally resistant. This resistance was overcome by increasing the drug exposure time. Inhibition of DNA synthesis by 5-min pretreatments with aphidicolin or hydroxyurea abolished the cytotoxicity of camptothecin without changing the level of camptothecin-induced DNA breaks. A good correlation was found between the degree of DNA synthesis inhibition by aphidicolin and the reduction of camptothecin cytotoxicity. In similar experiments performed with topoisomerase II inhibitors, aphidicolin prevented only partially against VP-16- and amsacrine-induced cytotoxicities, yet had no effect upon drug-induced DNA breaks. These results indicate that the production of topoisomerase-mediated DNA breaks by antitumor drugs is not sufficient for cell killing. Instead, an interference of moving DNA replication forks with drug-stabilized topoisomerase-DNA complexes is critical for cell death. The cytotoxicity of camptothecin seemed to be completely related to this process, while that of topoisomerase II inhibitors seemed to involve additional mechanisms in DC3F cells.

¹ To whom requests for reprints should be addressed, at Building 37, Room 5A19, National Cancer Institute, Bethesda, MD 20892.

Received 11/ 9/88. Revised 3/10/89. Revised 5/12/89. Revised 8/11/89. Accepted 8/18/89.

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