Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Clinical importance of DNA repair inhibitors in cancer therapy

Clinical importance of DNA repair inhibitors in cancer therapy The efficacy of cancer chemotherapy and radiotherapy relies on generation of DNA damage. Since intrinsic DNA repair pathways enable cancer cells to survive by repairing these damaged lesions, inactivation of DNA repair coupled with chemotherapy and radiotherapy has a potential to enhance the effect of these therapies. Small molecule compounds that inhibit specific DNA repair proteins have been developed, and early clinical trials are ongoing. While DNA repair inhibitors have been tried mostly as a part of combination therapies with cytotoxic agents, recent reports highlighted a new concept in cancer therapy where DNA repair inhibitors could be used as single agents to selectively kill cancer cells. This concept is based on the findings that cancer cells are frequently defective in particular DNA repair pathway(s) and the presumption that inhibition of the compensatory repair pathway(s) in such cells might be useful to kill them. For example, poly(ADP-ribose) polymerase (PARP) plays a critical role in DNA base-excision repair, and inactivation of this protein increases the number of single-strand breaks, leading to double-strand breaks that require to be repaired by homologous recombination (HR) mediated by BRCA1 and BRCA2. Recently, BRCA1- or BRCA2-defective tumour cells were shown to be sensitive to PARP inhibitors alone. This treatment may be tumour-specific because only the BRCA1−/− or BRCA2−/− tumours in the BRCA1+/− or BRCA2+/− patients are completely defective in HR repair. The following short review aims at summarizing the basic mechanisms of DNA repair and the therapeutic options using DNA repair inhibitors in cancer therapy. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

Clinical importance of DNA repair inhibitors in cancer therapy

Download PDF
6 pages

Loading next page...
 
/lp/springer-journals/clinical-importance-of-dna-repair-inhibitors-in-cancer-therapy-H1XHNBOi2e
Publisher
Springer Journals
Copyright
Copyright © 2009 by Springer-Verlag
Subject
Medicine & Public Health; Oncology; Medicine/Public Health, general
ISSN
1865-5041
eISSN
1865-5076
DOI
10.1007/s12254-008-0081-7
Publisher site
See Article on Publisher Site

Abstract

The efficacy of cancer chemotherapy and radiotherapy relies on generation of DNA damage. Since intrinsic DNA repair pathways enable cancer cells to survive by repairing these damaged lesions, inactivation of DNA repair coupled with chemotherapy and radiotherapy has a potential to enhance the effect of these therapies. Small molecule compounds that inhibit specific DNA repair proteins have been developed, and early clinical trials are ongoing. While DNA repair inhibitors have been tried mostly as a part of combination therapies with cytotoxic agents, recent reports highlighted a new concept in cancer therapy where DNA repair inhibitors could be used as single agents to selectively kill cancer cells. This concept is based on the findings that cancer cells are frequently defective in particular DNA repair pathway(s) and the presumption that inhibition of the compensatory repair pathway(s) in such cells might be useful to kill them. For example, poly(ADP-ribose) polymerase (PARP) plays a critical role in DNA base-excision repair, and inactivation of this protein increases the number of single-strand breaks, leading to double-strand breaks that require to be repaired by homologous recombination (HR) mediated by BRCA1 and BRCA2. Recently, BRCA1- or BRCA2-defective tumour cells were shown to be sensitive to PARP inhibitors alone. This treatment may be tumour-specific because only the BRCA1−/− or BRCA2−/− tumours in the BRCA1+/− or BRCA2+/− patients are completely defective in HR repair. The following short review aims at summarizing the basic mechanisms of DNA repair and the therapeutic options using DNA repair inhibitors in cancer therapy.

Journal

memo - Magazine of European Medical Oncology – Springer Journals

Published: Jan 1, 2008

References

  • DNA double-strand breaks: signaling, repair and the cancer connection
    Khanna, KK; Jackson, SP
  • Chromosomal stability and the DNA double-stranded break connection
    van Gent, DC; Hoeijmakers, JH; Kanaar, R
  • DNA repair pathways as targets for cancer therapy
    Helleday, T; Petermann, E; Lundin, C
  • DNA repair deficiency as a therapeutic target in cancer
    Martin, SA; Lord, CJ; Ashworth, A
  • DNA double-strand break repair: from mechanistic understanding to cancer treatment
    Helleday, T; Lo, J; van Gent, DC; Engelward, BP
  • Mechanism of homologous recombination: mediators and helicases take on regulatory functions
    Sung, P; Klein, H
  • Targeting base excision repair to improve cancer therapies
    Sharma, RA; Dianov, GL
  • A multistep damage recognition mechanism for global genomic nucleotide excision repair
    Sugasawa, K; Okamoto, T; Shimizu, Y
  • Suicide inactivation of the E. coli O6-methylguanine-DNA methyltransferase
    Lindahl, T; Demple, B; Robins, P
  • Repair of DNA interstrand cross-links
    Dronkert, MLG; Kanaar, R
  • Topoisomerase I inhibitors: camptothecins and beyond
    Pommier, Y
  • DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells
    Arnaudeau, C; Lundin, C; Helleday, T
  • Fanconi anemia and DNA replication repair
    Patel, KJ; Joenje, H
  • The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks
    Hanada, K; Budzowska, M; Davies, SL
  • DNA helicases required for homologous recombination and repair of damaged replication forks
    Wu, L; Hickson, ID
  • Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway
    Middleton, MR; Margison, GP
  • (ADP-ribose)n participates in DNA excision repair
    Durkacz, BW; Omidiji, O; Gray, DA
  • Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells
    de Murcia, JM; Niedergang, C; Trucco, C
  • Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination
    Schultz, N; Lopez, E; Saleh-Gohari, N
  • Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology
    Ratnam, K; Low, JA
  • ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models
    Donawho, CK; Luo, Y; Luo, Y
  • HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination
    Adimoolam, S; Sirisawad, M; Chen, J
  • SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization
    Ismail, IH; Martensson, S; Moshinsky, D
  • Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441
    Zhao, Y; Thomas, HD; Batey, MA
  • Targeting phosphoinositide 3-kinase: moving towards therapy
    Marone, R; Cmiljanovic, V; Giese, B
  • Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors
    Ranson, M; Middleton, MR; Bridgewater, J
  • Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma
    Ranson, M; Hersey, P; Thompson, D
  • A phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer
    Khan, OA; Ranson, M; Michael, M
  • The cyclin-dependent kinase inhibitor UCN-01 plus cisplatin in advanced solid tumors: a California cancer consortium phase I pharmacokinetic and molecular correlative trial
    Lara, PN; Mack, PC; Synold, T
  • Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study
    Hotte, SJ; Oza, A; Winquist, EW
  • Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM
    Hickson, I; Zhao, Y; Richardson, CJ
  • Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
    Farmer, H; McCabe, N; Lord, CJ
  • Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
    Bryant, HE; Schultz, N; Thomas, HD
  • Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers
    Sakai, W; Swisher, EM; Karlan, BY
  • Resistance to therapy caused by intragenic deletion in BRCA2
    Edwards, SL; Brough, R; Lord, CJ
  • Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance
    Swisher, EM; Sakai, W; Karlan, BY