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.
Keywords: topoisomerase, inhibitor, camptothecin, topotecan, anthracycline, anthracenedione, drug design
Medicinal Chemistry
Title: Topoisomerase Enzymes as Therapeutic Targets for Cancer Chemotherapy
Volume: 1 Issue: 4
Author(s): Gregory I. Giles and Ram P. Sharma
Affiliation:
Keywords: topoisomerase, inhibitor, camptothecin, topotecan, anthracycline, anthracenedione, drug design
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.
Export Options
About this article
Cite this article as:
Giles I. Gregory and Sharma P. Ram, Topoisomerase Enzymes as Therapeutic Targets for Cancer Chemotherapy, Medicinal Chemistry 2005; 1 (4) . https://dx.doi.org/10.2174/1573406054368738
DOI https://dx.doi.org/10.2174/1573406054368738 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Big Data and Genome Editing Technology: A New Paradigm of Cardiovascular Genomics
Current Cardiology Reviews Editorial (Thematic Issue: Modifying Cardiovascular Risk Factors: Current Opinion and Future Trends)
Current Pharmaceutical Design Beta-Blockers: Current State of Knowledge and Perspectives
Mini-Reviews in Medicinal Chemistry A Glance on the Role of Bacterial Siderophore from the Perspectives of Medical and Biotechnological Approaches
Current Drug Targets Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets
Current Pharmaceutical Design Cardiovascular Magnetic Resonance for Evaluation of Heart Involvement in ANCA-Associated Vasculitis. A Luxury or a Valuable Diagnostic Tool?
Inflammation & Allergy - Drug Targets (Discontinued) Disease-Specific iPS Cell Models in Neuroscience
Current Molecular Medicine Tracking Stem Cell Therapy in the Myocardium: Applications of Positron Emission Tomography
Current Pharmaceutical Design Prediction of Disease-Related Genes Based on Hybrid Features
Current Proteomics Methods for Identifying Cardiovascular Agents: A Review
Recent Patents on Cardiovascular Drug Discovery Coenzyme Q10 in Cardiovascular and Metabolic Diseases: Current State of the Problem
Current Cardiology Reviews Advanced Glycation End Products: Association with the Pathogenesis of Diseases and the Current Therapeutic Advances
Current Clinical Pharmacology Genetically Modified Endothelial Progenitor Cells in the Therapy of Cardiovascular Disease and Pulmonary Hypertension
Current Vascular Pharmacology Arrhythmias and Left Ventricular Hypertrabeculation/Noncompaction
Current Pharmaceutical Design Inflammatory Syndrome in Chronic Kidney Disease: Pathogenesis and Influence on Outcomes
Inflammation & Allergy - Drug Targets (Discontinued) Validity of Oxygen-Ozone Therapy as Integrated Medication Form in Chronic Inflammatory Diseases
Cardiovascular & Hematological Disorders-Drug Targets Retraction Note: Phytochemicals from Plants to Combat Cardiovascular Disease
Current Medicinal Chemistry Smoking and Cardiovascular System: Cellular Features of the Damage
Current Pharmaceutical Design Research Advancements in Porcine Derived Mesenchymal Stem Cells
Current Stem Cell Research & Therapy Melatonin Alleviates Pyroptosis of Retinal Neurons Following Acute Intraocular Hypertension
CNS & Neurological Disorders - Drug Targets