AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo.
AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo.
复制标题
DOI：
10.1038/bjc.1995.280
复制
发表时间：
1995-07
影响因子：
8.8
通讯作者：
Patterson LH
中科院分区：
文献类型：
--
作者：
McKeown SR;Hejmadi MV;McIntyre IA;McAleer JJ;Patterson LH
AQ4N (1,4-bis([2-(二甲氨基-N-氧化物)乙基]氨基)5,8-二羟基-蒽-9,10-二酮) 是一种新型烷基氨基蒽醌 N-氧化物，还原后形成稳定的 DNA 亲和细胞毒性化合物 AQ4。在携带 T50/80 乳腺癌的 B6D2F1 小鼠中研究了 AQ4N 的体内抗肿瘤功效。结合低压缺氧和放射（单次和多次）评估药物的效果。通过治疗后体重减轻评估全身毒性。 AQ4N 的结果较低，低于使用生物还原药物 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）获得的结果。 AQ4N 与低压缺氧联合使用可增强体内抗肿瘤作用，剂量增强比为 5.1。这与 AQ4N 在体内还原为 AQ4 从而增强抗肿瘤毒性的提议一致。当 AQ4N (200 mg kg-1) 与单剂量辐射 (12 Gy) 结合使用时，该药物与辐射具有附加相互作用。即使在放射治疗前 4 天至放射治疗后 6 小时内给药，也能获得这一结果。当 AQ4N (200 mg kg-1) 和放射 (5 x 3 Gy) 分次给药时，也显示出等效的抗肿瘤活性。总之，AQ4N 作为生物还原药物与分割放射治疗相结合显示出巨大的潜力。
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.