Topoisomerase I Poisons and Suppressors as Anticancer Drugs

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