Topoisomerase I poisons and suppressors as anticancer drugs.
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 benzophenanthridine 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 (beta-lapachone, diospyrin, topostatin, topostin, flavonoids) 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.
Bailly
C
C
INSERM Unité 524 and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France. bailly@lille.inserm.fr
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I