Abstract
Tumor resistance to cytotoxic chemotherapy drugs and their toxicity to normal cells are major clinical obstacles to anticancer therapy effectiveness. Alterations in various DNA repair pathways play a key role in the development of both mechanisms of drug resistance and toxicity. Since deregulation of the DNA damage response and alterations in DNA repair pathways are relatively common in human cancer, the knowledge of these alterations in cancer cells would be an important predictive factor for the clinical response to chemotherapy and a useful guide in designing an appropriate therapeutic strategy. This review is focused on the mismatch repair (MMR) pathway and the O6-methylguanine-DNA-methyltransferase (MGMT) repair protein. In particular, we examine how inactivation of these DNA repair mechanisms might affect the response of tumor cells to chemotherapy, with a special emphasis on agents inducing methylation and oxidative DNA damage and interstrand DNA cross-links (ICLs). In addition, we provide novel experimental evidence indicating that MMR is required for efficient repair of ICLs via stabilization of RAD51 containing repair intermediates. Finally, we discuss possible emerging therapeutical strategies for treating MMR-defective tumors.
Anti-Cancer Agents in Medicinal Chemistry
Title: Role of Mismatch Repair and MGMT in Response to Anticancer Therapies
Volume: 8 Issue: 4
Author(s): Ida Casorelli, Maria Teresa Russo and Margherita Bignami
Affiliation:
Abstract: Tumor resistance to cytotoxic chemotherapy drugs and their toxicity to normal cells are major clinical obstacles to anticancer therapy effectiveness. Alterations in various DNA repair pathways play a key role in the development of both mechanisms of drug resistance and toxicity. Since deregulation of the DNA damage response and alterations in DNA repair pathways are relatively common in human cancer, the knowledge of these alterations in cancer cells would be an important predictive factor for the clinical response to chemotherapy and a useful guide in designing an appropriate therapeutic strategy. This review is focused on the mismatch repair (MMR) pathway and the O6-methylguanine-DNA-methyltransferase (MGMT) repair protein. In particular, we examine how inactivation of these DNA repair mechanisms might affect the response of tumor cells to chemotherapy, with a special emphasis on agents inducing methylation and oxidative DNA damage and interstrand DNA cross-links (ICLs). In addition, we provide novel experimental evidence indicating that MMR is required for efficient repair of ICLs via stabilization of RAD51 containing repair intermediates. Finally, we discuss possible emerging therapeutical strategies for treating MMR-defective tumors.
Export Options
About this article
Cite this article as:
Casorelli Ida, Russo Teresa Maria and Bignami Margherita, Role of Mismatch Repair and MGMT in Response to Anticancer Therapies, Anti-Cancer Agents in Medicinal Chemistry 2008; 8 (4) . https://dx.doi.org/10.2174/187152008784220276
DOI https://dx.doi.org/10.2174/187152008784220276 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
- 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
-
Down Regulated Expression of Claudin-1 and Claudin-5 and Up Regulation of β-Catenin: Association with Human Glioma Progression
CNS & Neurological Disorders - Drug Targets Targeted Angiogenesis Therapy in Head and Neck Squamous Cell Carcinomas
Current Angiogenesis (Discontinued) Amplicons as Vaccine Vectors
Current Gene Therapy The Role for Oxidative Stress in Aberrant DNA Methylation in Alzheimer’s Disease
Current Alzheimer Research Synthetic Lethality to Overcome Cancer Drug Resistance
Current Medicinal Chemistry Oligonucleotides as Anticancer Agents: From the Benchside to the Clinic and Beyond
Current Pharmaceutical Design Pharmacological Applications of Antioxidants: Lights and Shadows
Current Drug Targets Current Perspectives of Healthy Mitochondrial Function for Healthy Neurons
Current Drug Targets On the Nature of the Tumor-Initiating Cell
Current Stem Cell Research & Therapy Targeting Ovarian Cancer-Initiating Cells
Anti-Cancer Agents in Medicinal Chemistry Structural and Mechanistic Bases of the Anticancer Activity of Natural Aporphinoid Alkaloids
Current Topics in Medicinal Chemistry T Cell Suicide Gene Therapy to Aid Haematopoietic Stem Cell Transplantation
Current Gene Therapy CYP4 Enzymes As Potential Drug Targets: Focus on Enzyme Multiplicity, Inducers and Inhibitors, and Therapeutic Modulation of 20- Hydroxyeicosatetraenoic Acid (20-HETE) Synthase and Fatty Acid ω- Hydroxylase Activities
Current Topics in Medicinal Chemistry Focused Microarray Analysis: Characterization of Phenomes by Gene Expression Profiling
Current Pharmacogenomics Recent Patents on Heat Shock Proteins Targeting Antibodies
Recent Patents on Anti-Cancer Drug Discovery Current Phthalocyanines Delivery Systems in Photodynamic Therapy: An Updated Review
Current Medicinal Chemistry Possibility of Non-Immunosuppressive Immunophilin Ligands as Potential Therapeutic Agents for Parkinsons Disease
Current Pharmaceutical Design Divergent Synthesis of Novel Dienylbenzothiazoles and Arylidenedibenzoxazepines and Evaluation of Their Antiproliferative and Cytotoxic Properties
Letters in Organic Chemistry Poly(ADP-Ribose) Polymerase Inhibitors: New Pharmacological Functions and Potential Clinical Implications
Current Pharmaceutical Design Brain Delivery Systems via Mechanism Independent of Receptor-Mediated Endocytosis and Adsorptive-Mediated Endocytosis
Current Pharmaceutical Biotechnology