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DNA topoisomerases as targets for chemotherapy
1Department of Pharmacology, Medical School, University of Texas Health Science Center, Houston 77225.
Abstract:
DNA topoisomerases are ubiquitous enzymes that alter the configuration or topology of DNA. These enzymes play an important role in replicational, recombinational, and transcriptional events and are a key to cell growth processes. A number of therapeutically useful drugs apparently exert their effects by interfering with DNA topoisomerization reactions. Several inhibitors of bacterial DNA topoisomerase II (DNA gyrase) have been developed. Most of these possess a 4-quinolone nucleus and are highly bactericidal for a variety of microorganisms; at therapeutically effective levels, these compounds do not inhibit the human topoisomerases. Other drugs, structurally distinct from the DNA gyrase inhibitors, inhibit the human type II DNA topoisomerase. These drugs, including m-AMSA and VP16-23, are proving useful in the treatment of several neoplasms.
Insights
DNA topoisomerases are vital enzymes for cell growth, influencing DNA replication and transcription. Inhibitors targeting bacterial DNA gyrase or human topoisomerase II offer therapeutic potential against infections and neoplasms.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- DNA topoisomerases are essential enzymes that regulate DNA topology, crucial for fundamental cellular processes like replication, recombination, and transcription.
- These enzymes are key targets for therapeutic intervention, with drugs designed to interfere with their activity.
- Inhibitors of bacterial DNA topoisomerase II (DNA gyrase) and human type II DNA topoisomerase have distinct structures and applications.
Purpose of the Study:
- To review the role of DNA topoisomerases in cellular functions.
- To discuss the development and therapeutic applications of DNA topoisomerase inhibitors.
- To differentiate between inhibitors of bacterial DNA gyrase and human topoisomerase II.
Main Methods:
- Literature review of DNA topoisomerase function and inhibition.
- Analysis of drug structures and their mechanisms of action.
- Examination of therapeutic outcomes for neoplastic and microbial diseases.
Main Results:
- Bacterial DNA gyrase inhibitors, primarily 4-quinolones, are bactericidal and selective, not affecting human topoisomerases.
- Human type II DNA topoisomerase inhibitors, such as m-AMSA and VP-16-213, are effective in treating certain cancers.
- These distinct drug classes highlight the therapeutic potential of targeting DNA topology in different disease contexts.
Conclusions:
- DNA topoisomerases are critical targets for antimicrobial and anticancer therapies.
- Selective inhibition of bacterial DNA gyrase offers a strategy for combating microbial infections.
- Targeting human topoisomerase II provides a viable approach for cancer treatment.