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Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

Phillips, Roger M. (2016) Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs. Cancer Chemotherapy and Pharmacology, 77 (3). pp. 441-457. ISSN 0344-5704

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Abstract

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Schools: School of Applied Sciences
Related URLs:
Depositing User: Roger Phillips
Date Deposited: 19 Nov 2015 12:09
Last Modified: 21 Nov 2016 22:42
URI: http://eprints.hud.ac.uk/id/eprint/26511

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