AQ4N: a new approach to hypoxia-activated cancer chemotherapy

Abstract

Summary Preclinical studies demonstrate that in vivo AQ4N enhances the anti-tumour effects of radiation and chemotherapeutic agents with a dose-modifying factor of approximately 2.0. With careful scheduling no, or very little, additional normal tissue toxicity should be observed. AQ4N is a bioreductive prodrug of a potent, stable, reduction product which binds non-covalently to DNA, facilitating antitumour activity in both hypoxic and proximate oxic tumour cells. AQ4N is clearly different in both its mechanism of action and potential bystander effect compared to previously identified bioreductive drugs. In particular AQ4N is the only bioreductive prodrug topoisomerase II inhibitor to enter clinical trials. Targeting this enzyme, which is crucial to cell division, may help sensitize tumours to repeated (fractionated) courses of radiotherapy. This is because in principle, the bioreduction product of AQ4N can inhibit the topoisomerase activity of hypoxic cells as they attempt to re-enter the cell cycle.

Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N)

“…AQ4N undergoes two sequential 2e -reductions, via the mono N-oxide AQM, to give AQ4, a potent topoisomerase II inhibitor. AQ4 is an oxygen-insensitive persistent cytotoxin that does not undergo redox cycling (20,21). It has, therefore, been hypothesized that AQ4N, once activated (to give AQ4), can diffuse to the surrounding cells and exert bystander effects (20).…”

“…AQ4 is an oxygen-insensitive persistent cytotoxin that does not undergo redox cycling (20,21). It has, therefore, been hypothesized that AQ4N, once activated (to give AQ4), can diffuse to the surrounding cells and exert bystander effects (20). Metabolic activation of AQ4N has previously been shown to be carried out by various cytochrome P450 isoforms under hypoxic conditions.…”

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

“…The aziridinydinitrobenzene derivative CB1954 (see also below and XV) and the alkylating nitroimidazole RSU1069 (X) were two compounds identified in early studies, and RSU1069 was selected for clinical trials by the Phase I/II Committee in 1982, and completed in 1986. Unmanageable nausea and vomiting was encountered with RSU1069 (Horwich et al, 1986); however, the bioreductive cytotoxins tirapazamine and AQ4N (XI) (Patterson and McKeown, 2000), the latter currently in clinical trials through the Phase I/II Committee, testify to the continued interest in the area of hypoxia-directed therapy. Tirapazamine has reached Phase III trials where initial results in combination with cisplatin have been encouraging.…”

Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N

“…Both drugs have shown efficacy in vivo in combination with radiation and established agents, cisplatin and cyclophosphamide. [3][4][5][6][7][8][9] The combination of TPZ with cisplatin in Phase III clinical trial has been encouraging. 3 Furthermore, AQ4N, has shown increased efficacy with less systemic toxicity than TPZ when combined with other agents in preclinical studies; 10,11 AQ4N is now in Phase I/II clinical trials.…”