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 of the therapeutic strategies designed to eradicate hypoxic cells in tumours is 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 (1) the ability of oxygen to either reverse or inhibit the activation process and (2) 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.
Highlights
One of the characteristic features of solid tumour biology is the presence of a poor and inadequate blood supply [1]
The origins of tumour hypoxia are linked to the abnormal vascular supply that develops within tumours, and there is a substantial body of evidence demonstrating that hypoxia is a common feature of most if not all-solid tumours
High hypoxia selectivity has been reported in a number of cell lines, and in vivo studies demonstrated that TPZ in combination with radiotherapy and cisplatin was highly effective against a range of human tumour xenografts [103] and TPZ entered clinical trial in early 1990s
Summary
One of the characteristic features of solid tumour biology is the presence of a poor and inadequate blood supply [1] This leads to the establishment of microenvironments that are characterised by gradients of oxygen tension, nutrients, extracellular pH, catabolites and reduced cell proliferation, all of which vary as a function of distance from a supporting blood vessel (Fig. 1). A third mechanism to explain the induction of hypoxia in tumours has been described, namely longitudinal arteriole gradients whereby oxygen-rich inflowing blood vessels branch and coalesce to form poorly oxygenated outflowing blood [3] In this model, hypoxia would be formed along the axis of the vessel over a multimillimetre range, which contrasts with the submillimetre distances typically associated with perfusion- and diffusion-limited hypoxia. Hypoxia is implicated in promoting resistance to apoptosis [4], suppression of DNA repair pathways and promotion of genomic instability [5] increased invasion and metastasis [6], promotion of angiogenesis [7], modulation of tyrosine kinase-mediated cell signalling pathways [8], evasion
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