Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets

Chalmers, A. J. , Lakshman, M., Chan, N. and Bristow, R. G. (2010) Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets. Seminars in Radiation Oncology, 20(4), pp. 274-281. (doi:10.1016/j.semradonc.2010.06.001)

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Publisher's URL: http://dx.doi.org/10.1016/j.semradonc.2010.06.001

Abstract

DNA double-strand breaks (DSBs) induced during clinical radiotherapy are potent inducers of cell death. Poly(ADP-ribose) polymerase (PARP)-1 is a 113-kD nuclear protein that binds to both single- and double-strand DNA breaks and is actively involved in DNA single-strand break repair and base excision repair. Recently, potent and specific chemical inhibitors of PARP activity have been developed that are effective tumor cell radiosensitizers in vitro and in vivo. Because of synthetic lethality, PARP inhibitors may be highly effective as a single agent in patients whose tumors have germline or somatic defects in DNA damage and repair genes (eg, ATM, BRCA1, BRCA2, and NBS1) or defects in genes involved in phosphatase and tensin homolog gene (PTEN) signaling. Defects in specific DNA repair pathways also appear to enhance the radiosensitizing effects of PARP inhibition. In addition to inherent genetics, tumor cells may also be preferentially sensitized to radiotherapy by diverse mechanisms, including proliferation-dependent radiosensitization, targeting of the endothelium and tumor vasculature, and increased sensitivity to PARP inhibitors within repair-deficient hypoxic cells. Because biologically active doses of PARP inhibitors caused minimal toxicity in phase I to II clinical trials, careful scheduling of these agents in combination with radiotherapy may maintain the therapeutic ratio and increase tumor radiocurability.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Chalmers, Professor Anthony
Authors: Chalmers, A. J., Lakshman, M., Chan, N., and Bristow, R. G.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Clinical Specialities
Journal Name:Seminars in Radiation Oncology
Publisher:Elsevier
ISSN:1053-4296
ISSN (Online):1532-9461
Published Online:08 September 2010
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
563531Overcoming treatment resistance in glioblastoma multiforme by tumour specific inhibition of DNA repairAnthony ChalmersMedical Research Council (MRC)G0802755Pathology