From Professor L. H. Patterson, FRSC
SIR,-Airley et al's article on hypoxia and disease (PJ, April 29, pp666-73) rightly identified the therapeutic opportunities this pathophysiological condition creates.
Unfortunately, it neglected to inform your readers of the status of AQ4N, the most promising anticancer bioreductive drug in preclinical development. AQ4N is a unique bioreductively activated prodrug.1,2 This is because it is the only agent currently described that is converted to a persistent anticancer agent unaffected by tumour reoxygenation. In other words, AQ4N will continue to act even after the acute hypoxic episodes described in Airley et al's article. It is also the only bioreductive prodrug topoisomerase II inhibitor in preclinical development. Targeting this enzyme is especially important in hypoxic, ie, radiation resistant, tumour cells, since its inhibition (by AQ4N) synchronises cell growth. Therefore AQ4N will sensitise tumours to the repeated (fractionated) courses of radiation commonly used in radiotherapy.3
AQ4N is well documented as a very effective enhancer of radiotherapy3,4 as well as cis-platin and cyclophosphamide chemotherapy.4–6 Its promise as the next generation bioreductive agent is supported by preclinical studies that show AQ4N performs better than tirapazamine.3,4
Your readers will be interested to know that AQ4N is about to enter Cancer Research Campaign directed phase I clinical trials to be conducted in Leicester and Oxford. AQ4N offers an exciting development in bioreductive drug justification and is a direct result of extensive academic research originating from UK schools of pharmacy.
Laurence Patterson
Professor of Medicinal Chemistry and Head of Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London
| 1. Patterson LH. Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA-binding agents - a new class of bioreductive agent. Cancer Metastasis Rev 1993;12: 119-34. |
| 2. McKeown SR, Hejmadi MV, McIntyre IA, McAleer JJA, Patterson LH. AQ4N - an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo. Br J Cancer 1995;72:76-81. |
| 3. McKeown SR, Friery OP, McIntyre IA, Hejmadi MV, Patterson LH, Hirst DG. Evidence for a therapeutic gain when AQ4N or tirapazamine is combined with radiation. Br J Cancer 1996; 74(Suppl):S39-S42. |
| 4. Hejmadi MV, McKeown SR, Friery OP, McIntyre IA, Patterson LH, Hirst DG. DNA damage following combination of radiation with the bioreductive drug AQ4N: possible selective toxicity to oxic and hypoxic tumour cells. Br J Cancer 1996;73:499-505. |
| 5. McKeown SR, Friery O, Gallagher R, Murray M, Clarke C, Patterson LH et al. Enhancement of cyclophosphamide anti-tumour activity with bioreductive drugs AQ4N and tirapazamine. Br J Cancer 1998;78: 45. |
| 6. Patterson LH, Ruparelia K, Double J, Bibby M, Graham M, Cole S et al. Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated antitumour agent. Br J Cancer (In press). |