McKeown S R, Hejmadi M V, McIntyre I A, McAleer J J, Patterson L H
School of Biomedical Sciences, University of Ulster at Jordanstown, UK.
Br J Cancer. 1995 Jul;72(1):76-81. doi: 10.1038/bjc.1995.280.
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.
AQ4N（1,4-双([2-(二甲氨基-N-氧化物)乙基]氨基)-5,8-二羟基蒽醌-9,10-二酮）是一种新型的烷基氨基蒽醌N-氧化物，经还原后可形成稳定的具有DNA亲和性的细胞毒性化合物AQ4。在携带T50/80乳腺癌的B6D2F1小鼠中研究了AQ4N的体内抗肿瘤疗效。评估了该药物与低压缺氧及放疗（单次和多次分割）联合使用的效果。通过治疗后体重减轻来评估全身毒性。AQ4N的全身毒性较低，低于生物还原药物RSU 1069（1-[3-氮丙啶基-2-羟丙基]-2-硝基咪唑）和SR 4233（替拉扎明，3-氨基-1,2,4-苯并三嗪-1,4-二氧化物）。AQ4N与低压缺氧联合使用时，其体内抗肿瘤效果得到增强，剂量增强比为5.1。这与AQ4N在体内被还原为AQ4从而增强抗肿瘤毒性的观点一致。当AQ4N（200 mg·kg-1）与单次剂量放疗（12 Gy）联合使用时，该药物与放疗显示出相加作用。即使在放疗前4天至放疗后6小时给药，也能得到这种效果。当AQ4N（200 mg·kg-1）和放疗（5×3 Gy）均采用分割方案给药时，也显示出等效的抗肿瘤活性。总之，AQ4N作为一种可与分割放疗联合使用的生物还原药物具有显著潜力。
