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

AQ4 (1,4-Bis-([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxyanthracene -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 activat ed in, and is preferentially toxic to, hypoxic cells in tumours. Five murin e tumours (MAC16, MAC26, NT, SCCVII and RIF-1) have been used to investigat e the anti-tumour effects of AQ4N. In only one tumour (MAC16) was AQ4N show n to be active as a single agent. However, when combined with methods to in crease the hypoxic tumour fraction in RIF-1 (by physical clamping) and MAC2 6 tumours (using hydralazine) there was a substantial enhancement in anti-t umour effect. Notably, RIF-1 tumours treated with AQ4N (250 mg kg(-1)) foll owed 15 min later by physically occluding the blood supply to the tumour fo r 90 min, resulted in a 13-fold increase in growth delay. When combined wit h 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 radi ation treatment. In combination with chemotherapy it is shown that AQ4N pot entiates 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 p rovides indirect evidence that in the combination chemotherapy experiments there is same tumour selectivity in the enhanced action of the drugs. (C) 2 000 Cancer Research Campaign.