The Design of Drugs that Target Tumour Hypoxia

William A. Denny

doi:10.1071/CH04051

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The Design of Drugs that Target Tumour Hypoxia

William A. Denny ^A

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^A Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland, New Zealand (e-mail: b.denny@auckland.ac.nz).

Bill Denny received his Ph.D. and D.Sc. degrees in chemistry from the University of Auckland, where he is director of the Auckland Cancer Society Research Center. He has participated in the development of seven anticancer drugs to clinical trials. His currect research interests include signal transduction inhibitors and hypoxia-activated prodrugs.

Australian Journal of Chemistry 57(9) 821-828 https://doi.org/10.1071/CH04051
Submitted: 1 March 2004 Accepted: 19 April 2004 Published: 1 September 2004

Abstract

The occurrence of hypoxia in solid tumours is increasingly recognized as a limiting factor in the success of both radiotherapy and chemotherapy treatment, but at the same time offers a tumour-specific phenomenon for the activation of prodrugs. However, the design of clinically useful prodrugs that can be selectively activated in hypoxic cells has proved elusive. Specific reasons (activation by oxygen-insensitive two-electron reductases) have been proposed for the failure of quinone-based prodrugs, but a more general contributing factor may be inappropriate clinical trial design, and the failure to understand the critical importance of drug properties, such as efficient extra-vascular diffusion of the prodrug and back-diffusion of the activated drug in the tumour. Activation of prodrugs by therapeutic radiation and the use of hypoxia-selective gene therapy vectors, such as Clostridia, are exciting new mechanisms for prodrug research to explore, but are in much earlier stages of evaluation.

Acknowledgments

Thanks to all my colleagues in this endeavour in the Auckland Cancer Society Research Centre and elsewhere, but especially to Bill Wilson and Martin Brown.

References

The Design of Drugs that Target Tumour Hypoxia

Abstract

Acknowledgments

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