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Topoisomerase I poisons and suppressors as anticancer drugs
1INSERM Unité 524 and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France. bailly@lille.inserm.fr
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 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.
Insights
Topoisomerase I inhibitors are novel antitumor agents. This review details topoisomerase I poisons and suppressors, including their origins, chemistry, and mechanisms for cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Topoisomerase I inhibitors represent a significant class of anticancer drugs.
- Camptothecin derivatives, such as topotecan and irinotecan, are key examples that target the topoisomerase I-DNA complex.
- Other inhibitors include DNA minor groove binders, intercalators, and natural products.
Purpose of the Study:
- To review the diverse families of topoisomerase I poisons and suppressors.
- To present the origin, chemical nature, and mechanisms of action of these inhibitors.
- To discuss the relationship between drug-DNA binding and topoisomerase I inhibition.
Main Methods:
- Literature review of topoisomerase I inhibitors.
- Analysis of chemical structures and origins of compounds.
- Examination of mechanisms of action, including DNA cleavage stimulation and complex formation inhibition.
Main Results:
- Identification of multiple classes of topoisomerase I inhibitors: poisons (camptothecins, minor groove binders, intercalators) and suppressors (natural products).
- Detailed description of how these agents interact with the topoisomerase I-DNA complex.
- Exploration of the link between drug-DNA interactions and enzyme inhibition.
Conclusions:
- Topoisomerase I inhibitors offer a novel approach to cancer therapy.
- Understanding the diverse mechanisms of these agents is crucial for drug development.
- Further research into drug-DNA binding and enzyme interactions can lead to more effective anticancer strategies.