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Identification of Topoisomerase I as the Cytotoxic Target of the Protoberberine Alkaloid Coralyne¹

Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 [B. G., M. M. S., C. Y., H-Y. W., L. F. L.], and Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08855 [D. M., E. J. L.]

Protoberberine alkaloids (coralyne and its derivatives), which exhibit antileukemic activity in animal models, have been shown to be potent inducers of topoisomerase (topo) I-DNA cleavable complexes using purified recombinant human DNA topo I. Different from the structurally similar benzophenanthridine alkaloid nitidine (a dual poison of both topos I and II), coralyne and its derivatives have marginal poisoning activity against DNA topo II. Yeast cells expressing human DNA topo I are shown to be specifically sensitive to killing by coralyne derivatives and nitidine, suggesting that cellular DNA topo I is their cytotoxic target. Two human camptothecin-resistant cell lines, CPT-K5 and A2780/CPT-2000, which are known to express highly camptothecin-resistant topo I, are only marginally resistant to coralyne derivatives and nitidine. Purification of human topo I from Escherichia coli cells overexpressing CPT-K5 recombinant topo I has demonstrated similar marginal cross-resistance to nitidine. It seems possible to develop coralyne and nitidine derivatives as new topo I-targeted therapeutics to overcome aspects of camptothecin-related resistance.

¹ Supported by NIH Grant CA39662 (L. F. L.) and a fellowship grant from the Johnson & Johnson Discovery Research Fund (E. J. L.).

² To whom requests for reprints should be addressed, at Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635.

Received 12/ 1/95. Accepted 4/ 9/96.

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