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Topoisomerase enzymes as therapeutic targets for cancer chemotherapy

Topoisomerase enzymes as therapeutic targets for cancer chemotherapy
Topoisomerase enzymes as therapeutic targets for cancer chemotherapy
The topoisomerase enzymes are essential for DNA metabolism, where they act to adjust the number of supercoils in DNA, a key requirement in the cellular processes of transcription and replication. Their enzymatic mechanism creates transient nicks (type I) or breaks (type II) in the double stranded DNA polymer, allowing DNA to be converted between topological isomers. Humans possess both types of topoisomerase enzymes, however the two types utilize very different enzymatic mechanisms. Both type I and type II topoisomerases have been identified as clinically important targets for cancer chemotherapy and their inhibitors are central components in many therapeutic regimes. Over the course of the last 30 years inhibitors with extensive structural diversity have been developed through a combination of drug screening and rational design programs. Simultaneously much emphasis has been placed upon establishing the mechanisms of action of both classes of topoisomerase enzyme. Crucial structural insights have come from the crystal structure of topoisomerase I, while modelling comparisons are beginning to map out a possible framework for topoisomerase II action. This review discusses these recent advances in the fields of enzyme mechanism and inhibitor design. We also address the development of drug resistance and dose-limiting side effects as well as cover alternative methods in drug delivery.
topoisomerase, inhibitor, camptothecin, topotecan, anthracycline, anthracenedione, drug design
383-394
Giles, Gregory I.
0e3c10cd-6d8c-4f95-8fd8-45259415226d
Sharma, Ram P.
aef51420-fc90-49d8-b04c-142214c2961a
Giles, Gregory I.
0e3c10cd-6d8c-4f95-8fd8-45259415226d
Sharma, Ram P.
aef51420-fc90-49d8-b04c-142214c2961a

Giles, Gregory I. and Sharma, Ram P. (2005) Topoisomerase enzymes as therapeutic targets for cancer chemotherapy. Medicinal Chemistry, 1 (4), 383-394. (doi:10.2174/1573406054368738).

Record type: Article

Abstract

The topoisomerase enzymes are essential for DNA metabolism, where they act to adjust the number of supercoils in DNA, a key requirement in the cellular processes of transcription and replication. Their enzymatic mechanism creates transient nicks (type I) or breaks (type II) in the double stranded DNA polymer, allowing DNA to be converted between topological isomers. Humans possess both types of topoisomerase enzymes, however the two types utilize very different enzymatic mechanisms. Both type I and type II topoisomerases have been identified as clinically important targets for cancer chemotherapy and their inhibitors are central components in many therapeutic regimes. Over the course of the last 30 years inhibitors with extensive structural diversity have been developed through a combination of drug screening and rational design programs. Simultaneously much emphasis has been placed upon establishing the mechanisms of action of both classes of topoisomerase enzyme. Crucial structural insights have come from the crystal structure of topoisomerase I, while modelling comparisons are beginning to map out a possible framework for topoisomerase II action. This review discusses these recent advances in the fields of enzyme mechanism and inhibitor design. We also address the development of drug resistance and dose-limiting side effects as well as cover alternative methods in drug delivery.

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More information

Published date: 2005
Additional Information: Review Article
Keywords: topoisomerase, inhibitor, camptothecin, topotecan, anthracycline, anthracenedione, drug design

Identifiers

Local EPrints ID: 25074
URI: https://eprints.soton.ac.uk/id/eprint/25074
PURE UUID: 4d3f125b-91b2-4b2b-841b-8cffbd8277d7

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Date deposited: 06 Apr 2006
Last modified: 17 Jul 2017 16:12

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Contributors

Author: Gregory I. Giles
Author: Ram P. Sharma

University divisions

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