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Prodrug Strategies for Targeting Tumour Hypoxia

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Hypoxia and Cancer

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

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Abstract

Tumour hypoxia is a critically important, but elusive, target in cancer therapy; the importance of eliminating hypoxic cells is underscored by their central roles in tumour progression and resistance to cytotoxic chemotherapy and radiotherapy. While many molecular targets may offer synthetic lethal interactions with hypoxia, the development of prodrugs that are activated to generate cytotoxins by one-electron (1e) reduction in hypoxic cells represents a more direct approach. Although conceptually simple, significant challenges need to be overcome to achieve useful therapeutic activity. These include designing prodrugs able to diffuse efficiently into hypoxic tissue, avoidance of off-target (oxygen-insensitive) two-electron (2e) reduction, maximizing bystander effects from diffusion of the active metabolites to exploit severely hypoxic regions in tumours and (critically) the development of predictive biomarkers for what is in fact a multifaceted target (comprising hypoxia, activating reductases and the molecular determinants of sensitivity to the active metabolites). Here we provide an overview of recent progress towards these goals in the context of four classes of hypoxia-activated prodrugs (HAPs) in clinical trial or in advanced preclinical development, namely benzotriazine di-oxides (tirapazamine and SN30000), the dinitrobenzamide mustard (DNBM) PR-104, the phosphoramidate mustard TH-302 and nitrochloromethylbenzindoline (nitroCBI) prodrugs of potent DNA minor groove alkylators.

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Authors and Affiliations

  1. Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, 1142, Auckland, New Zealand

    William R. Wilson PhD, Kevin O. Hicks, Jingli Wang & Frederik B. Pruijn

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  1. William R. Wilson PhD
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  2. Kevin O. Hicks
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  3. Jingli Wang
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  4. Frederik B. Pruijn
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Correspondence to William R. Wilson PhD .

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

    Giovanni Melillo

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Wilson, W., Hicks, K., Wang, J., Pruijn, F. (2014). Prodrug Strategies for Targeting Tumour Hypoxia. 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_13

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