Abstract
DNA Mismatch Repair (MMR) deficiency results in resistance to platinating and alkylating agents, DNA minor groove binders, inhibitors of topoisomerases and antimetabolites. The cellular MMR pathway, involving hMLH1 and MSH2, detects and repairs DNA frame shifts replication errors and regulates recombination events. Tumour cells are able to cope with DNA damage caused by chemotherapy as long as the MMR-process is disabled and hence there is a need to develop agents that (i) restore MMR proficiency or (ii) are hypersensitive in cells that are irreversibly MMR deficient. Decitabine is suggested to restore MMR function by reversal of gene promoter hypermethylation of hMLH1. However, when MMR is deficient due to gene mutation it is not feasible to design agents, since the absence of functional proteins that constitute the MMR machinery are not available as targets. The evidence that resistance to chemotherapy is associated with hMSH2 and/or hMLH1 deficiency has revealed a new paradigm for drug discovery of agents that positively exploit this phenotype to therapeutic advantage. Even more attractive is the development of agents that are hypersensitive in the absence of functional MMR to enable even more effective treatment. In this regard, established agents such as mitomycin C, camptothecin or novel hydroxyethylaminoanthraquinones may represent opportunities for exploitation of MMR-deficiency in tumour cells.
Keywords: dna mismatch repair, multidrug resistance, hmsh, hmlh, topoisomerase, colorectal cancer, ovarian cancer, anthraquinone
Current Topics in Medicinal Chemistry
Title: DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents
Volume: 5 Issue: 12
Author(s): Klaus Pors and Laurence H. Patterson
Affiliation:
Keywords: dna mismatch repair, multidrug resistance, hmsh, hmlh, topoisomerase, colorectal cancer, ovarian cancer, anthraquinone
Abstract: DNA Mismatch Repair (MMR) deficiency results in resistance to platinating and alkylating agents, DNA minor groove binders, inhibitors of topoisomerases and antimetabolites. The cellular MMR pathway, involving hMLH1 and MSH2, detects and repairs DNA frame shifts replication errors and regulates recombination events. Tumour cells are able to cope with DNA damage caused by chemotherapy as long as the MMR-process is disabled and hence there is a need to develop agents that (i) restore MMR proficiency or (ii) are hypersensitive in cells that are irreversibly MMR deficient. Decitabine is suggested to restore MMR function by reversal of gene promoter hypermethylation of hMLH1. However, when MMR is deficient due to gene mutation it is not feasible to design agents, since the absence of functional proteins that constitute the MMR machinery are not available as targets. The evidence that resistance to chemotherapy is associated with hMSH2 and/or hMLH1 deficiency has revealed a new paradigm for drug discovery of agents that positively exploit this phenotype to therapeutic advantage. Even more attractive is the development of agents that are hypersensitive in the absence of functional MMR to enable even more effective treatment. In this regard, established agents such as mitomycin C, camptothecin or novel hydroxyethylaminoanthraquinones may represent opportunities for exploitation of MMR-deficiency in tumour cells.
Export Options
About this article
Cite this article as:
Pors Klaus and Patterson H. Laurence, DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents, Current Topics in Medicinal Chemistry 2005; 5 (12) . https://dx.doi.org/10.2174/156802605774370883
DOI https://dx.doi.org/10.2174/156802605774370883 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
The Delivery of Biologically Active (Therapeutic) Peptides and Proteins into Cells
Current Medicinal Chemistry OX40:OX40L Axis: Emerging Targets for Immunotherapy of Human Disease
Current Immunology Reviews (Discontinued) The ATP-driven Hsp60 Machinery: Biological and Clinical Implications
Current Immunology Reviews (Discontinued) Alternative Splicing in Chronic Myeloid Leukemia (CML): A Novel Therapeutic Target?
Current Cancer Drug Targets Using Small Molecule GSK3β Inhibitors to Treat Inflammation
Current Medicinal Chemistry Plasticity and Maintenance of Hematopoietic Stem Cells During Development
Recent Patents on Biotechnology High-level Soluble Expression, Purification, and Functional Characterization of the Recombinant Human Leukemia Inhibitory Factor: A Potential General Strategy for the Recombinant Expression of Cytokines Consisting of Four α-Helices in a Bundle
Protein & Peptide Letters Patent Selections:
Recent Patents on Anti-Cancer Drug Discovery Patent Analysis as a Tool for Research Planning: Study on Natural Based Therapeutics Against Cancer Stem Cells
Recent Patents on Anti-Cancer Drug Discovery Plasmid-Mediated Muscle-Targeted Gene Therapy for Circulating Therapeutic Protein Replacement: A Tale of the Tortoise and the Hare?
Current Gene Therapy Medical and Dental Implications of Down Syndrome: A Review Part 1: General and Craniofacial Characteristic
Applied Clinical Research, Clinical Trials and Regulatory Affairs Effects of Drug Transporters on Pharmacological Responses and Safety
Current Drug Metabolism Rheumatic Manifestations in Malignancy
Current Rheumatology Reviews Perspectives Offered by Single-Domain Antibodies in Clinical Diagnostic of Pediatric Tumors
Current Medicinal Chemistry Promoters and Control Elements: Designing Expression Cassettes for Gene Therapy
Current Gene Therapy Characterisation of Small Supernumerary Marker Chromosomes (sSMC) in Human
Current Genomics Resveratrol and Neurodegenerative Diseases: Activation of SIRT1 as the Potential Pathway towards Neuroprotection
Current Neurovascular Research Herpesvirus Saimiri-Based Gene Delivery Vectors
Current Gene Therapy Immune Therapy of Multiple Sclerosis - Future Strategies
Current Pharmaceutical Design An Update on Natural Occurrence and Biological Activity of Chromones
Current Medicinal Chemistry