AQ4N - AN ALKYLAMINOANTHRAQUINONE N-OXIDE SHOWING BIOREDUCTIVE POTENTIAL AND POSITIVE INTERACTION WITH RADIATION IN-VIVO

AQ4N -(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxy- anthracene-9,1 0-dione) is a novel alkylaminoanthraquinone N-oxide which, on reductio n, forms a stable DNA affinic cytotoxic compound AQ4. The in vivo anti -tumour efficacy of AQ4N was investigated in B6D2F(1) mice bearing the T50/80 mammary carcinoma. The effect of the drug was evaluated in com bination with hypobaric hypoxia and with radiation (single and multipl e fractions). Systemic toxicity was assessed by weight loss post treat ment. This was low for AQ4N and was less than that obtained with the b ioreductive drugs, RSU 1069 1-[3-aziridinyl-2-hydroxypropyl]-2-nitroim idazole) and SR 4233 (Tirapazamine, 3-amino-1,2,4-benzotriazine-1,4-di oxide). The anti-tumour effect of AQ4N was potentiated in vivo by comb ination with hypobaric hypoxia with a dose enhancement ratio of 5.1. T his is consistent with the proposal that AQ4N was reduced in vivo to A Q4, 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 eve n if the drug was administered from 4 days before to 6 h after radiati on treatment. Equivalent anti-tumour activity was also shown when both AQ4N (200 mg kg(-1)) and radiation (5 x 3 Gy) were administered in fr actionated schedules. In conclusion, AQ4N shows significant potential as a bioreductive drug for combination with fractionated radiotherapy.