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Relationship between the Intracellular Effects of Camptothecin and the Inhibition of DNA Topoisomerase I in Cultured L1210 Cells¹

Department of Molecular Pharmacology, SmithKline and French Laboratories, Philadelphia, Pennsylvania 19101

Results of filter elution assays of lesions produced in the DNA of cultured L1210 cells by the antineoplastic alkaloid camptothecin support the notion that topoisomerase I is an intracellular target of this drug. One to 10 µM camptothecin induced DNA single-strand, but not double-strand, breaks when incubated with intact cells or with their isolated nuclei. Approximately one half of the strand breakage was protein concealed, as judged by filter elution. Camptothecin-induced, protein-concealed DNA strand breaks disappeared rapidly after drug removal. DNA-protein cross-links were generated by camptothecin with frequencies approximately equal to those of protein-concealed DNA strand breaks. It is likely that camptothecin can inhibit topoisomerase I in intact cells in a manner similar to that in which other antineoplastic agents such as amsacrine or teniposide inhibit topoisomerase II. DNA-breaking lesions other than those resulting from trapped topoisomerase I-DNA complexes may also be generated by camptothecin. The yields of DNA strand breaks induced by camptothecin, amsacrine, or teniposide were approximately doubled when cells were incubated for 16 h with 3-aminobenzamide, an inhibitor of poly(ADP ribosylation) of proteins, prior to 1-h exposure to the antineoplastic compounds. 3-Aminobenzamide also enhanced the cytotoxic action of camptothecin, amsacrine, and teniposide. These results suggest that protein-concealed strand breaks can be lethal lesions and that intracellular topoisomerase I and II activity may be regulated coordinately through poly(ADP ribosylation).

¹ Part of this work was supported by Grant 1-U01-C40884-01 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at the Department of Molecular Pharmacology, SmithKline and French Laboratories, 1500 Spring Garden Street, L-511, Philadelphia, PA 19101.

Received 5/16/86. Revised 9/18/86. Revised 12/ 3/86. Accepted 12/29/86.

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