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Topoisomerase I Alteration in a Camptothecin-resistant Cell Line Derived from Chinese Hamster DC3F Cells in Culture

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

Camptothecin-resistant DC3F Chinese hamster lung fibroblast cell lines were obtained after mutagenic treatment with ethylmethanesulfonate and subsequent exposure to 1 µM camptothecin (CPT). The most resistant cell line, which was obtained after exposure to CPT for 10 days, was designated DC3F/C-10. Comparison of 50% inhibitory concentration values after 8-h CPT treatments showed that DC3F/C-10 cells were 134-fold resistant to CPT. Resistance was associated with marked reduction of CPT-induced DNA single-strand breaks and DNA-protein cross-links. This reduction was not due to reduced amounts of immunoreactive DNA topoisomerase I protein, although nuclear extracts from DC3F/C-10 cells had less enzyme catalytic activity than those from DC3F cells. Also, fast protein liquid chromatography-purified DNA topoisomerase I from DC3F/C-10 had lower specific catalytic activity than that from DC3F cells. DNA topoisomerase I from DC3F/C-10 was resistant to inhibition of catalytic activity and induction of DNA cleavage by CPT. These results suggest that CPT resistance in DC3F/C-10 cells is due to qualitative alteration of DNA topoisomerase I.

¹ To whom requests for reprints should be addressed, at Building 37, Room 5C27, National Institutes of Health, Bethesda, MD 20892.

Received 7/11/91. Accepted 1/15/92.

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