AQ4N (1,4-bis([2-(dimethylamino-N-
oxide)ethyl]amino)5,8-dihydroxy-
anthracene-9,10-dione) is a novel alkylaminoanthraquinone N-
oxide which, on reduction, forms a stable
DNA affinic cytotoxic compound AQ4. The in vivo anti-tumour efficacy of
AQ4N was investigated in B6D2F1 mice bearing the T50/80 mammary
carcinoma. The effect of the
drug was evaluated in combination with hypobaric
hypoxia and with radiation (single and multiple fractions). Systemic toxicity was assessed by
weight loss post treatment. This was low for
AQ4N and was less than that obtained with the bioreductive drugs,
RSU 1069 (1-[3-aziridinyl-2-hydroxypropyl]-2-
nitroimidazole) and
SR 4233 (Tirapazamine, 3-amino-1,2,4-benzotriazine-1,4-dioxide). The anti-tumour effect of
AQ4N was potentiated in vivo by combination with hypobaric
hypoxia with a dose enhancement ratio of 5.1. This is consistent with the proposal that
AQ4N was reduced in vivo to AQ4, resulting in enhanced anti-tumour toxicity. When
AQ4N (200 mg kg-1) was combined with single dose radiation (12 Gy) the
drug was shown to have an additive interaction with radiation. This was obtained even if the
drug was administered from 4 days before to 6 h after
radiation treatment. Equivalent anti-tumour activity was also shown when both
AQ4N (200 mg kg-1) and radiation (5 x 3 Gy) were administered in fractionated schedules. In conclusion,
AQ4N shows significant potential as a bioreductive
drug for combination with fractionated
radiotherapy.