Abstract
This article will present the rationale for combining chemical inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) with conventional cytotoxic agents to improve the treatment of glioblastoma. After a brief review of the current therapeutic options for these aggressive tumours, the possible reasons for their resistance to radiation and chemotherapy will be discussed, highlighting the important role of DNA damage response pathways in many key resistance mechanisms. The dose-limiting toxicities associated with radiation and chemotherapy treatment will be described in order to illustrate the importance of tumour specificity in any attempt to increase the effectiveness of conventional treatments. There will then be a summary of the reasons why targeting DNA repair pathways might achieve tumour specific sensitization. After a brief summary of the key DNA damage response pathways, the biology, biochemistry and pharmacology of PARP and the existing PARP inhibitors will be presented. The major part of the review will cover the effects of combining PARP inhibitors with radiation and chemotherapy in vitro and in vivo, commenting on the underlying mechanisms and indicating where the data are predictive of tumour specific sensitization. Finally, we will consider specific scenarios where PARP inhibitors might contribute to the treatment of glioblastoma patients, discuss the challenges and opportunities associated with early phase clinical testing of these agents, and describe the clinical trials that are either underway or in development.
Keywords: Glioblastoma, poly(ADP-ribose) polymerase, DNA repair, PARP inhibitors, radiosensitizers, chemosensitizers.
Anti-Cancer Agents in Medicinal Chemistry
Title: Overcoming Resistance of Glioblastoma to Conventional Cytotoxic Therapies by the Addition of PARP Inhibitors
Volume: 10 Issue: 7
Author(s): Anthony J. Chalmers
Affiliation:
Keywords: Glioblastoma, poly(ADP-ribose) polymerase, DNA repair, PARP inhibitors, radiosensitizers, chemosensitizers.
Abstract: This article will present the rationale for combining chemical inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) with conventional cytotoxic agents to improve the treatment of glioblastoma. After a brief review of the current therapeutic options for these aggressive tumours, the possible reasons for their resistance to radiation and chemotherapy will be discussed, highlighting the important role of DNA damage response pathways in many key resistance mechanisms. The dose-limiting toxicities associated with radiation and chemotherapy treatment will be described in order to illustrate the importance of tumour specificity in any attempt to increase the effectiveness of conventional treatments. There will then be a summary of the reasons why targeting DNA repair pathways might achieve tumour specific sensitization. After a brief summary of the key DNA damage response pathways, the biology, biochemistry and pharmacology of PARP and the existing PARP inhibitors will be presented. The major part of the review will cover the effects of combining PARP inhibitors with radiation and chemotherapy in vitro and in vivo, commenting on the underlying mechanisms and indicating where the data are predictive of tumour specific sensitization. Finally, we will consider specific scenarios where PARP inhibitors might contribute to the treatment of glioblastoma patients, discuss the challenges and opportunities associated with early phase clinical testing of these agents, and describe the clinical trials that are either underway or in development.
Export Options
About this article
Cite this article as:
J. Chalmers Anthony, Overcoming Resistance of Glioblastoma to Conventional Cytotoxic Therapies by the Addition of PARP Inhibitors, Anti-Cancer Agents in Medicinal Chemistry 2010; 10 (7) . https://dx.doi.org/10.2174/187152010793498627
DOI https://dx.doi.org/10.2174/187152010793498627 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...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
-
Epigenetic Remodeling of Chromatin Architecture: Exploring Tumor Differentiation Therapies in Mesenchymal Stem Cells and Sarcomas
Current Stem Cell Research & Therapy Animal Venoms have Potential to Treat Cancer
Current Topics in Medicinal Chemistry The Effects of Dietary Supplements that Overactivate the Nrf2/ARE System
Current Medicinal Chemistry Vitamin D Metabolites and/or Analogs: Which D for Which Patient?
Current Vascular Pharmacology PHB in Cardiovascular and Other Diseases: Present Knowledge and Implications
Current Drug Targets Challenges in the Correct Assessment of a Case of Aggressive Thyroid Carcinoma with Synchronous Breast Cancer: A Case Report and Review of the Literature of Essential Role of Radiopharmaceuticals
Current Radiopharmaceuticals Aflibercept (VEGF-TRAP): The Next Anti-VEGF Drug
Inflammation & Allergy - Drug Targets (Discontinued) General Aspects of Metal Toxicity
Current Medicinal Chemistry A Sialic Acid-Specific Lectin from the Mushroom Paecilomyces Japonica that Exhibits Hemagglutination Activity and Cytotoxicity
Protein & Peptide Letters Phosphorothioate Oligonucleotides: Effectiveness and Toxicity
Current Drug Targets Scintigraphic Imaging of Inflammatory Processes
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents MicroRNA Polymorphisms, MicroRNA Pharmacogenomics and Cancer Susceptibility
Current Pharmacogenomics and Personalized Medicine Design of Telomerase Inhibitors for the Treatment of Cancer
Current Pharmaceutical Design UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase- 6 (pp-GalNAc-T6): Role in Cancer and Prospects as a Drug Target
Current Cancer Drug Targets Editorial (Thematic Issue: Treatment of Cancer in the Elderly)
Anti-Cancer Agents in Medicinal Chemistry Chemical and Clinical Development of Darinaparsin, a Novel Organic Arsenic Derivative
Anti-Cancer Agents in Medicinal Chemistry The Therapeutic Potential of ADAM15
Current Pharmaceutical Design Meta Analysis of Advanced Cancer Survival Data Using Lognormal Parametric Fitting: A Statistical Method to Identify Effective Treatment Protocols
Current Pharmaceutical Design The Role of Mass Spectrometry in the “Omics” Era
Current Organic Chemistry Fluorinated Natural Products with Clinical Significance
Current Topics in Medicinal Chemistry