Abstract
Modern cancer therapies, mainly ionizing radiation and certain classes of chemotherapies target DNA. Although these treatments disrupt the genome, their rationale is clear. They prevent cancer cells from dividing and proliferating. Nevertheless, cancer cells can survive by over-activating a wide range of DNA repair pathways to eliminate the induced damage. In this context, DNA repair mechanisms are considered to be a vital target to improve cancer therapy and reduce the resistance to many DNA damaging agents currently in use as standard-of-care treatments. Here, we focus on two important DNA repair pathways, namely base excision repair (BER) and nucleotide excision repair (NER). Specifically, our focus is on two protein targets that are linked to the hallmark “relapse” and “drug resistance” phenomena. These are Excision Repair Cross-Complementation Group 1 (ERCC1), and DNA polymerase beta (pol β). The former is a key player in NER, while the latter is the error-prone polymerase of BER. Our objective is to list all known inhibitors for the two targets and provide an overview of the great efforts that were made in their discovery. While in the DNA pol β case more than sixty inhibitors were identified, very few inhibitors have been discovered on the ERCC1 side. It is hoped that this review will assist in the discovery of novel, potent and specific drug candidates aimed at improving existing cancer therapies including ionizing radiation, bleomycin, monofunctional alkylating agents and cisplatin.
Keywords: DNA damaging agents, BER, NER, DNA polymerase beta, cancer, inhibitor, ERCC1, XPF, XPA, ionizing radiation, c hemotherapies target DNA
Current Topics in Medicinal Chemistry
Title:DNA Repair Inhibitors: The Next Major Step to Improve Cancer Therapy
Volume: 12 Issue: 12
Author(s): Khaled Barakat, Melissa Gajewski and Jack A. Tuszynski
Affiliation:
Keywords: DNA damaging agents, BER, NER, DNA polymerase beta, cancer, inhibitor, ERCC1, XPF, XPA, ionizing radiation, c hemotherapies target DNA
Abstract: Modern cancer therapies, mainly ionizing radiation and certain classes of chemotherapies target DNA. Although these treatments disrupt the genome, their rationale is clear. They prevent cancer cells from dividing and proliferating. Nevertheless, cancer cells can survive by over-activating a wide range of DNA repair pathways to eliminate the induced damage. In this context, DNA repair mechanisms are considered to be a vital target to improve cancer therapy and reduce the resistance to many DNA damaging agents currently in use as standard-of-care treatments. Here, we focus on two important DNA repair pathways, namely base excision repair (BER) and nucleotide excision repair (NER). Specifically, our focus is on two protein targets that are linked to the hallmark “relapse” and “drug resistance” phenomena. These are Excision Repair Cross-Complementation Group 1 (ERCC1), and DNA polymerase beta (pol β). The former is a key player in NER, while the latter is the error-prone polymerase of BER. Our objective is to list all known inhibitors for the two targets and provide an overview of the great efforts that were made in their discovery. While in the DNA pol β case more than sixty inhibitors were identified, very few inhibitors have been discovered on the ERCC1 side. It is hoped that this review will assist in the discovery of novel, potent and specific drug candidates aimed at improving existing cancer therapies including ionizing radiation, bleomycin, monofunctional alkylating agents and cisplatin.
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Cite this article as:
Barakat Khaled, Gajewski Melissa and A. Tuszynski Jack, DNA Repair Inhibitors: The Next Major Step to Improve Cancer Therapy, Current Topics in Medicinal Chemistry 2012; 12 (12) . https://dx.doi.org/10.2174/156802612801319070
DOI https://dx.doi.org/10.2174/156802612801319070 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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