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Hypoxia and Cancer pp 21–41Cite as

Hypoxia and the DNA Damage Response

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Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Gradients of hypoxia occur in most solid tumors. Cells found in these regions are associated with the most aggressive and therapy-resistant fractions of the tumor. Severe levels of hypoxia (< 0.1 % O2) have been found to induce a unique DNA damage response (DDR) that includes both ATR- and ATM-mediated signaling. The consequences of the hypoxia-induced DDR include p53-dependent apoptosis and maintenance of replication fork integrity. Interestingly, the hypoxia-induced DDR occurs in the absence of detectable single- or double-strand breaks and in a background of repressed DNA repair. Inhibition of DNA repair in hypoxic cells has been proposed as a mechanism contributing to the increased genomic instability found in hypoxia. Furthermore, an increasing number of novel agents that target the DDR have been described and some are already undergoing clinical testing. Evidence from preclinical studies suggests that the use of some of these agents would be effective at targeting tumor cells in hypoxic regions.

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Authors and Affiliations

  1. The Department of Oncology, The Cancer Research UK/MRC Gray Institute for Radiation Oncology and Biology, The University of Oxford, OX3 7DQ, Oxford, UK

    Monica M. Olcina & Ester M. Hammond

Authors
  1. Monica M. Olcina
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  2. Ester M. Hammond
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Correspondence to Ester M. Hammond .

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Editors and Affiliations

  1. Bristol-Myers Squibb, Princeton, New Jersey, USA

    Giovanni Melillo

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Olcina, M., Hammond, E. (2014). Hypoxia and the DNA Damage Response. In: Melillo, G. (eds) Hypoxia and Cancer. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9167-5_2

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