Prospects for bioreductive drug development

Bioreductive drugs are inactive prodrugs that are converted into potent cytotoxins under conditions of either low oxygen tension or in the presence of high levels of specific reductases. The biochemical basis for selectivity relies on the ability of oxygen to reverse the activation process and the presence of elevated reductase levels in some tumour types. Key criteria for an ideal bioreductive drug should include poor activity against aerobic cells, activation over a broad range of oxygen tensions and, penetration through the aerobic fraction of cells. In addition, the active drug should be capable of killing non-proliferating cells. Numerous compounds are currently at various stages of drug development but Mitomycin C, which is generally considered to be the prototype bioreductive drug, is the only one in clinical use today. Of the drugs currently being evaluated clinically, tirapazamine has definite clinical activity against a variety of solid tumours when used in combination with cisplatin. Other drugs, such as EO9 and various nitroimidazoles, have not been impressive in the clinic and further development is required to improve properties such as drug delivery in the case of indoloquinones. A novel approach to exploiting tumour hypoxia is the development of a gene-directed enzyme prodrug therapy (GDEPT) strategy, where a gene encoding for a prodrug activating enzyme has been placed under the control of a hypoxia responsive promoter sequence. It is generally recognised that bioreductive drugs must be directed towards patients whose tumours have hypoxic regions or have appropriate enzymological characteristics. In terms of identifying tumour hypoxia, there has been considerable progress in the development of nitroimidazole based hypoxia markers that can be detected either via non-invasive or invasive procedures. Another strategy currently undergoing preclinical evaluation is the use of agents that modulate tumour blood flow and synergistic effects have been reported between bioreductive drugs and photodynamic therapy or inhibitors of nitric oxide synthase for example. The development of clinically useful bioreductive drugs depends therefore on the expertise of scientists and clinicians with varying backgrounds. The purpose of this review is to describe and critically assess recent developments in this field, with particular emphasis being placed on drug development and strategies aimed at optimising bioreductive drug activity.