Abstract
Irinotecan and topotecan are derivatives of the naturally occurring cytotoxic compound camptothecin that are used in the treatment of patients with colorectal cancer, either as single agents or in combination with radiotherapy and/or other chemotherapy drugs. They are inhibitors of DNA topoisomerase I (Top I) and exert their cytotoxic effects in replicating cells by inducing DNA strand breaks. A wide range of DNA repair proteins is involved in the recognition and repair of these breaks, and depletion or inhibition of some of these proteins increases the cytotoxic effects of Top I inhibitors. Building on these laboratory observations, ongoing translational research is aiming to establish whether this mechanistic information can be used to improve the treatment of patients with certain types of cancer. Two potential strategies are under investigation: (1) individualising treatment by evaluating levels and/or patterns of expression of DNA repair proteins that predict clinical response to Top I inhibitors, and (2) developing small molecule inhibitors of these repair enzymes to overcome tumour resistance and improve outcomes. This review summarises the current status of these research endeavours, focusing on the key roles of tyrosyl DNA phosphodiesterase 1 (Tdp1) and poly(ADP-ribose) polymerase (PARP), and examines the pre-clinical and clinical data that support the potential value of these and other DNA repair proteins as predictive markers and therapeutic targets. Since irinotecan is increasingly being combined with radiotherapy, the potential for these proteins to act as predictive biomarkers for both Top I inhibitors and radiation is proposed, and the possibility of synergistic potentiation of chemoradiation regimes by Tdp1 and/or PARP inhibitors is considered.
Keywords: Topoisomerase I, tyrosyl DNA phosphodiesterase 1, poly(ADP-ribose) polymerase, colorectal cancer, irinotecan, radiation therapy, chemoradiation, biomarkers, Irinotecan and topotecan
Current Medicinal Chemistry
Title:DNA Repair and Resistance to Topoisomerase I Inhibitors: Mechanisms, Biomarkers and Therapeutic Targets
Volume: 19 Issue: 23
Author(s): M. Alagoz, D. C. Gilbert, S. El-Khamisy and A. J. Chalmers
Affiliation:
Keywords: Topoisomerase I, tyrosyl DNA phosphodiesterase 1, poly(ADP-ribose) polymerase, colorectal cancer, irinotecan, radiation therapy, chemoradiation, biomarkers, Irinotecan and topotecan
Abstract: Irinotecan and topotecan are derivatives of the naturally occurring cytotoxic compound camptothecin that are used in the treatment of patients with colorectal cancer, either as single agents or in combination with radiotherapy and/or other chemotherapy drugs. They are inhibitors of DNA topoisomerase I (Top I) and exert their cytotoxic effects in replicating cells by inducing DNA strand breaks. A wide range of DNA repair proteins is involved in the recognition and repair of these breaks, and depletion or inhibition of some of these proteins increases the cytotoxic effects of Top I inhibitors. Building on these laboratory observations, ongoing translational research is aiming to establish whether this mechanistic information can be used to improve the treatment of patients with certain types of cancer. Two potential strategies are under investigation: (1) individualising treatment by evaluating levels and/or patterns of expression of DNA repair proteins that predict clinical response to Top I inhibitors, and (2) developing small molecule inhibitors of these repair enzymes to overcome tumour resistance and improve outcomes. This review summarises the current status of these research endeavours, focusing on the key roles of tyrosyl DNA phosphodiesterase 1 (Tdp1) and poly(ADP-ribose) polymerase (PARP), and examines the pre-clinical and clinical data that support the potential value of these and other DNA repair proteins as predictive markers and therapeutic targets. Since irinotecan is increasingly being combined with radiotherapy, the potential for these proteins to act as predictive biomarkers for both Top I inhibitors and radiation is proposed, and the possibility of synergistic potentiation of chemoradiation regimes by Tdp1 and/or PARP inhibitors is considered.
Export Options
About this article
Cite this article as:
Alagoz M., C. Gilbert D., El-Khamisy S. and J. Chalmers A., DNA Repair and Resistance to Topoisomerase I Inhibitors: Mechanisms, Biomarkers and Therapeutic Targets, Current Medicinal Chemistry 2012; 19 (23) . https://dx.doi.org/10.2174/092986712802002590
DOI https://dx.doi.org/10.2174/092986712802002590 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
- Announcements
Related Articles
-
Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways
Current Neuropharmacology MicroRNA in Cervical Carcinogenesis: Window of Therapeutic Potential
Current Women`s Health Reviews Ubiquitin Carboxyl Hydrolase L1 Significance for Human Diseases
Protein & Peptide Letters Highlights in Peptide Nanoparticle Carriers Intended to Oral Diseases
Current Topics in Medicinal Chemistry A Brief Evaluation of Tumor Imaging in Mice with 99mTc-glucarate Including a Comparison with 18F-FDG
Current Radiopharmaceuticals Patent Selections:
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Prospects of Applying Enhanced Semi-Empirical QM Methods for 2101 Virtual Drug Design
Current Medicinal Chemistry Modulation of Stem Cell Differentiation by the Influence of Nanobiomaterials/ Carriers
Current Stem Cell Research & Therapy Revisiting Non-Cancer Drugs for Cancer Therapy
Current Topics in Medicinal Chemistry Review: Circulating microRNAs in Predicting the Prognosis of Gastrointestinal Cancers
Current Biomarkers (Discontinued) C-Reactive Protein: Interaction with the Vascular Endothelium and Possible Role in Human Atherosclerosis
Current Pharmaceutical Design Array-Based Approaches for the Identification of Epigenetic Silenced Tumor Suppressor Genes
Current Genomics Targeting MUC15 Protein in Cancer: Molecular Mechanisms and Therapeutic Perspectives
Current Cancer Drug Targets Development of Fourth Generation ABC Inhibitors from Natural Products: A Novel Approach to Overcome Cancer Multidrug Resistance
Anti-Cancer Agents in Medicinal Chemistry Purine and Pyrimidine Pathways as Targets in Plasmodium falciparum
Current Topics in Medicinal Chemistry Recent Patents Relating to Tumor Suppressor Genes
Recent Patents on DNA & Gene Sequences The Molecular Basis of Class Side Effects Due to Treatment with Inhibitors of the VEGF/VEGFR Pathway
Current Clinical Pharmacology Hexosomes: A Novel Drug Delivery System
Current Drug Delivery Nanomedicine to Overcome Cancer Multidrug Resistance
Current Drug Metabolism What Makes Y Family Pols Potential Candidates for Molecular Targeted Therapies and Novel Biotechnological Applications
Current Molecular Medicine