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Topoisomerase I Poisons and Suppressors as Anticancer Drugs

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Abstract:

Inhibitors of topoisomerase I constitute a novel family of antitumor agents. The camptothecin derivatives topotecan and irinotecan represent new weapons in our arsenal for battling human cancer. These two drugs act specifically at the level of the topoisomerase I-DNA complex and stimulate DNA cleavage. This mechanism of action is not restricted to the camptothecins. Numerous topoisomerase I poisons including DNA minor groove binders such as Hoechst 33258 and DNA intercalators such as ben-zophenanthridine alkaloids and indolocarbazole derivatives have been discovered and developed. Another important group of topoisomerase I inhibitors contains drugs which prevent or reverse topoisomerase I-DNA complex formation. Many of these topoisomerase I suppressors are natural products (b-lapachone, diospyrin, topostatin, topostin, favonoids) which are believed to interact directly with the enzyme. This review is concerned with the different families of topoisomerase I poisons and suppressors. Their origin, chemical nature and mechanism of action are presented. The relationships between drug binding to DNA and topoisomerase I inhibition are discussed.

Keywords: DNA Cleavage; DNA intercalators; DNA minor groove binders; Hoechst 33258; Topotecan TPT Hycamtin; anthracyclines; anticancer Drugs; antitumor agents; camptotecin derivatives topotecan; camptothecins; diospyrin; doxorubicin adriamycin; enzyme; epipodophyllotoxins; favonoids; human cancer; indolocarbazole derivatives; irinotecan; mappia foetida; natural products lapcone; streptomycetes; suppressors; topoisomerase I DNA complex; topoisomerase I poisons; topoisomerase I suppressors; topostin; vincaalcaloids; zophenanthridine alkaloids

Document Type: Review Article

DOI: https://doi.org/10.2174/0929867003375489

Publication date: 2000-01-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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