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Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

Patterson, LH, McKeown, Stephanie, Ruparella, K, Double, JA, Bibby, MC, Cole, S and Stratford, IJ (2000) Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. BRITISH JOURNAL OF CANCER, 82 (12). pp. 1984-1990. [Journal article]

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Abstract

AQ4 (1,4-Bis-([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxyanthracen e-9, 10-dione) is a prod rug designed to be excluded from cell nuclei until bioreduced in hypoxic cells to AQ4, a DNA intercalator and topoisomerase It poison. Thus, AQ4N is a highly selective bioreductive drug that is activated in, and is preferentially toxic to, hypoxic cells in tumours. Five murine tumours (MAC16, MAC26, NT, SCCVII and RIF-1) have been used to investigate the anti-tumour effects of AQ4N. In only one tumour (MAC16) was AQ4N shown to be active as a single agent. However, when combined with methods to increase the hypoxic tumour fraction in RIF-1 (by physical clamping) and MAC26 tumours (using hydralazine) there was a substantial enhancement in anti-tumour effect. Notably, RIF-1 tumours treated with AQ4N (250 mg kg(-1)) followed 15 min later by physically occluding the blood supply to the tumour for 90 min, resulted in a 13-fold increase in growth delay. When combined with radiation or chemotherapy, AQ4N substantially increased the effectiveness of these modalities in a range of in vivo model systems. AQ4N potentiates the action of radiation in both a drug and radiation dose-dependent manner. Further the enhancement observed is schedule-independent with AQ4N giving similar effects when given at any time within 16 h before or after the radiation treatment. In combination with chemotherapy it is shown that AQ4N potentiates the activity of cyclophosphamide, cisplatin and thiotepa. Both the chemotherapeutic drugs and AQ4N are given at doses which individually are close to their estimated maximum tolerated dose (data not included) which provides indirect evidence that in the combination chemotherapy experiments there is same tumour selectivity in the enhanced action of the drugs. (C) 2000 Cancer Research Campaign.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Pharmaceutical Science and Practice
ID Code:4335
Deposited By:Professor Stephanie McKeown
Deposited On:21 Dec 2009 12:13
Last Modified:01 Jun 2011 16:49

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