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PARP Inhibitors and Cancer Therapy

  • Chapter
Poly(ADP-Ribosyl)ation

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

Abstract

The compelling evidence for the role of poly(ADP-ribose) polymerase(s) (PARP) in the cellular reaction to genotoxic stress was the stimulus to develop inhibitors as therapeutic agents to potentiate DNA-damaging anticancer therapies. The earliest inhibitors, the benzamides, developed in the 1980s provided “proof of principle” evidence that such an approach was feasible but they lacked the potency and specificity for advanced preclinical evaluation. Over the last two decades potent PARP inhibitors have been developed using structure activity relationships (SAR) and crystal structure analysis. These approaches have identified key desirable features for potent inhibitor-enzyme interactions. The resulting PARP inhibitors are up to 1,000 times more potent than the classical benzamides. These novel potent inhibitors have helped define the therapeutic potential of PARP inhibition. They significantly enhance the in vitro cytotoxicity of DNA monofunctional alkylating agents e.g., temozolomide, topoisomerase I poisons and ionising radiation. PARP inhibitors increase the antitumour activity of these three classes of anticancer agents in vivo, in some cases resulting in complete tumour regression. On the basis of these extremely promising preclinical data, clinical trials with a PARP inhibitor, in combination with temozolomide, commenced in June 2003 in the UK. This trial will allow the evaluation of PARP inhibition as a therapeutic manoeuvre in cancer for the first time.

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  1. Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne, UK

    Nicola J. Curtin

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Curtin, N.J. (2006). PARP Inhibitors and Cancer Therapy. In: Poly(ADP-Ribosyl)ation. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-36005-0_18

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