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Exploiting the Achilles heel of cancer: the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in BRCA2-defective cancer

Lookup NU author(s): Suzanne Kyle, Huw ThomasORCiD, Dr Jane Mitchell, Professor Nicola CurtinORCiD

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Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates DNA single-strand break-base excision repair to maintain genomic stability. Inhibition or loss of PARP activity leads to a recombinogenic phenotype characterized by increased sister chromatid exchange. Deficiency in homologous recombination (HR) owing to loss of BRCA1 or BRCA2 is associated with hereditary cancers of the breast, ovary, pancreas and prostate. We investigated the therapeutic potential of PARP inhibitors in HR and BRCA2-defective cells. We exposed cells defective in the HR component XRCC3 (irs1SF) and BRCA2 (V-C8) and their parental (AA8, V79) or deficiency corrected (CXR3, V-C8+B2) cells to the PARP inhibitors NU1025 and AG14361. Mice bearing BRCA2-deficient and BRCA2-proficient tumours were treated with AG14361. All HR-defective cells were hypersensitive to normally non-cytotoxic concentrations of PARP inhibitors. Cells lacking BRCA2 were 20 times more sensitive to PARP inhibitor-induced cytotoxicity. Three out of five BRCA2-defective xenografts responded to the potent PARP inhibitor, AG14361, and one tumour regressed completely, compared with non-responses in the BRCA2-proficient tumours treated with AG14361 or any mice treated with vehicle control. Untreated PARP-1(-/-) mouse embryo fibroblasts (MEFs) accumulated more DNA double-strand breaks than did PARP-1(+/+) MEFs. We believe the underlying cytotoxic mechanism is due to PARP inhibitor-mediated suppression of repair of DNA single-strand breaks, which are converted to DNA double-strand breaks at replication. These replication-associated double-strand breaks, which are normally repaired by HR, become cytotoxic in cells defective in HR. Using a DNA repair inhibitor alone to selectively kill a tumour represents an exciting new concept in cancer therapy.


Publication metadata

Author(s): Kyle S, Thomas HD, Mitchell J, Curtin NJ

Publication type: Article

Publication status: Published

Journal: British Journal of Radiology

Year: 2008

Volume: 81

Issue: Special Issue 1

Pages: S6-S11

Print publication date: 01/01/2008

ISSN (print): 0007-1285

ISSN (electronic): 1748-880X

Publisher: British Institute of Radiology

URL: http://dx.doi.org/10.1259/bjr/99111297

DOI: 10.1259/bjr/99111297


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