Format

Send to

Choose Destination
Br J Cancer. 2016 May 10;114(10):1071-7. doi: 10.1038/bjc.2016.79. Epub 2016 Apr 12.

Hypoxia-activated prodrugs: paths forward in the era of personalised medicine.

Author information

1
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
2
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland, New Zealand.
3
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
4
Department of Radiation Oncology, University of Toronto, Toronto, ON M5S 1A1, Canada.
5
Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A1, Canada.

Abstract

Tumour hypoxia has been pursued as a cancer drug target for over 30 years, most notably using bioreductive (hypoxia-activated) prodrugs that target antineoplastic agents to low-oxygen tumour compartments. Despite compelling evidence linking hypoxia with treatment resistance and adverse prognosis, a number of such prodrugs have recently failed to demonstrate efficacy in pivotal clinical trials; an outcome that demands reflection on the discovery and development of these compounds. In this review, we discuss a clear disconnect between the pathobiology of tumour hypoxia, the pharmacology of hypoxia-activated prodrugs and the manner in which they have been taken into clinical development. Hypoxia-activated prodrugs have been evaluated in the manner of broad-spectrum cytotoxic agents, yet a growing body of evidence suggests that their activity is likely to be dependent on the coincidence of tumour hypoxia, expression of specific prodrug-activating reductases and intrinsic sensitivity of malignant clones to the cytotoxic effector. Hypoxia itself is highly variable between and within individual tumours and is not treatment-limiting in all cancer subtypes. Defining predictive biomarkers for hypoxia-activated prodrugs and overcoming the technical challenges of assaying them in clinical settings will be essential to deploying these agents in the era of personalised cancer medicine.

PMID:
27070712
PMCID:
PMC4865974
DOI:
10.1038/bjc.2016.79
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center