AQ4N: a new approach to hypoxia-activated cancer chemotherapy

Preclinical studies demonstrate that in vivo AQ4N enhances the anti-tumour effects of radiation and chemotherapeutic agents with a dose-modifying fact or of approximately 2.0. With careful scheduling no, or very little, additi onal normal tissue toxicity should be observed. AQ4N is a bioreductive prod rug of a potent, stable, reduction product which binds non-covalently to DN A, facilitating antitumour activity in both hypoxic and proximate oxic tumo ur cells. AQ4N is clearly different in both its mechanism of action and pot ential bystander effect compared to previously identified bioreductive drug s. In particular AQ4N is the only bioreductive prodrug topoisomerase II inh ibitor to enter clinical trials. Targeting this enzyme, which is crucial to cell division, may help sensitize tumours to repeated (fractionated) cours es of radiotherapy. This is because in principle, the bioreduction product of AQ4N can inhibit the topoisomerase activity of hypoxic cells as they att empt to re-enter the cell cycle. (C) 2000 Cancer Research Campaign.