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Topoisomerases, new targets in cancer chemotherapy
J G Zijlstra1, S de Jong, E G de Vries
1Department of Internal Medicine, University Hospital Groningen, The Netherlands.
Abstract:
The enzymes involved in the regulation of the three-dimensional structure of DNA, topoisomerase I and II, are important for the handling of DNA during vital cellular processes such as translation, transcription and mitosis. The enzymes are currently being studied intensively, they are being biochemically characterized and their mechanism of action is now better understood. Empirically discovered antitumor drugs appear to interfere with these enzymes, especially topoisomerase II. The DNA-topoisomerase II complex, which is an intermediate in the normal enzyme pathway, is stabilized by the drug and forms a 'cleavable complex', which appears to be cytotoxic. The drugs involved are, e.g. anthracyclines, epipodophyllotoxins and acridines. The central role of this enzyme offers the cell an opportunity for the development of resistance by down-regulation of this enzyme or the production of resistant mutants, provided the adaptation does not hamper other vital cell functions. Knowledge of the working mechanism and the cellular regulation of the topoisomerases might lead to the selection of most effective drugs and treatment schedules, and to circumvention of drug resistance.
Insights
Topoisomerase enzymes regulate DNA structure for cell processes. Certain anticancer drugs target topoisomerase II, forming cytotoxic complexes but potentially leading to drug resistance.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Topoisomerases I and II are crucial enzymes regulating DNA's three-dimensional structure.
- These enzymes are essential for DNA handling during vital cellular processes like transcription, translation, and mitosis.
Purpose of the Study:
- To explore the mechanism of action of topoisomerases, particularly topoisomerase II.
- To understand how empirically discovered antitumor drugs interact with topoisomerases.
- To investigate the cellular mechanisms of drug resistance related to topoisomerases.
Main Methods:
- Biochemical characterization of topoisomerase enzymes.
- Analysis of drug interactions with DNA-topoisomerase complexes.
- Study of cellular adaptation and resistance mechanisms.
Main Results:
- Antitumor drugs, including anthracyclines, epipodophyllotoxins, and acridines, stabilize the DNA-topoisomerase II complex, forming a cytotoxic 'cleavable complex'.
- Cells can develop resistance to these drugs by down-regulating topoisomerase II or through resistant mutations.
Conclusions:
- Understanding topoisomerase mechanisms and regulation is key to developing effective anticancer drugs.
- Knowledge of these enzymes can guide the selection of optimal drug treatments and schedules.
- Strategies to circumvent drug resistance can be informed by the study of topoisomerase function and cellular adaptation.