Banoxantrone dihydrochloride (AQ4N dihydrochloride) is an oxygen-depleted activated topoisomerase II inhibitor, AQ4N binds to DNA in a non-covalent manner and promotes antitumor activity of hypoxic and hypoxic tumor cells[1-4].
AQ4N(0-0.25 mM;24h) showed 8-fold higher cytotoxicity under hypoxia than normoxia in cultures of 9L rat gliosarcoma and H460 human non-small-cell lung carcinoma cells[5].
AQ4N(200 mg/kg; i.p.; 30 minutes before radiation) was combined with radiation, considerable DNA damage was detected in T50/80 tumors implanted in BDF mice after immediate excision[2,6].Activation of AQ4N cytotoxicity in mice requires extensive and prolonged tumor hypoxia[5]. AQ4N inhibited HMEC-1 cell contacts on Matrigel, HMEC-1 cell invasion, and sprouting in rat aorta explants. When AQ4N (20 mg/kg) was given in vivo for 5 days, microvessels disappeared in LNCaP tumors grown in a dorsal skin flap[7].
References:
[1]. Newell DR, Searle KM, Westwood NB, Burtles SS; Cancer Research UK Phase I/II Clinical Trials Committee. Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK. Br J Cancer. 2003 Aug 4;89(3):437-54. doi: 10.1038/sj.bjc.6601106. PMID: 12888809; PMCID: PMC2394365.
[2]. Hejmadi MV, McKeown SR, et,al. DNA damage following combination of radiation with the bioreductive drug AQ4N: possible selective toxicity to oxic and hypoxic tumour cells. Br J Cancer. 1996 Feb;73(4):499-505. doi: 10.1038/bjc.1996.87. PMID: 8595165; PMCID: PMC2074454.
[3]. Patterson LH, McKeown SR, et,al. Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. Br J Cancer. 2000 Jun;82(12):1984-90. doi: 10.1054/bjoc.2000.1163. PMID: 10864207; PMCID: PMC2363261.
[4]. Patterson LH, McKeown SR. AQ4N: a new approach to hypoxia-activated cancer chemotherapy. Br J Cancer. 2000 Dec;83(12):1589-93. doi: 10.1054/bjoc.2000.1564. PMID: 11104551; PMCID: PMC2363465.
[5]. Manley E Jr, Waxman DJ. Impact of tumor blood flow modulation on tumor sensitivity to the bioreductive drug banoxantrone. J Pharmacol Exp Ther. 2013 Feb;344(2):368-77. doi: 10.1124/jpet.112.200089. Epub 2012 Nov 28. PMID: 23192656; PMCID: PMC3558827.
[6]. McKeown SR, Hejmadi MV, et,al. AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo. Br J Cancer. 1995 Jul;72(1):76-81. doi: 10.1038/bjc.1995.280. PMID: 7599069; PMCID: PMC2034137.
[7]. O'Rourke M, Ward C, et,al. Evaluation of the antiangiogenic potential of AQ4N. Clin Cancer Res. 2008 Mar 1;14(5):1502-9. doi: 10.1158/1078-0432.CCR-07-1262. PMID: 18316575.
Banoxantrone dihydrochloride (AQ4N dihydrochloride) 是一种缺氧活化拓扑异构酶 II 抑制剂，AQ4N 以非共价方式与 DNA 结合，促进缺氧和缺氧肿瘤细胞的抗肿瘤活性[1-4]。
AQ4N(0-0.25 mM;24h) 在 9L 大鼠神经胶质肉瘤和 H460 人非小细胞肺癌细胞培养物中表现出缺氧条件下比常氧条件下高 8 倍的细胞毒性[5]。
AQ4N （200 mg/kg；i.p.；放疗前 30 分钟）与放疗相结合，在立即切除后植入 BDF 小鼠的 T50/80 肿瘤中检测到相当大的 DNA 损伤 [2,6]。在小鼠中激活 AQ4N 细胞毒性需要广泛和长期肿瘤缺氧[5]。 AQ4N 抑制基质胶上的 HMEC-1 细胞接触、HMEC-1 细胞侵袭和大鼠主动脉外植体的发芽。体内给予 AQ4N (20 mg/kg) 5 天后，生长在背侧皮瓣的 LNCaP 肿瘤中微血管消失[7]。