Amifostine, an inorganic thiophosphate, is a selective broad-spectrum cytoprotector of normal tissues[1]. Amifostine is dephosphorylated by alkaline phosphatase in the body to form the active metabolite WR-1065, which scavenges oxygen free radicals and enhances the DNA repair process [2]. Amifostine has been widely used to reduce the severity of acute oral mucositis caused by radiation[3].
In vitro, Amifostine treatment for 5 days significantly inhibited the proliferation of myelodysplastic syndrome (MDS) cells, with an IC50 value of 14μM[4]. Treatment with 100μg/ml Amifostine for 12 hours inhibited apoptosis of 32D cells and enhanced the nuclear level of NF-κB/Rel[5]. Amifostine treatment for 12 days at a concentration of 1mM significantly inhibited the proliferation of Dami cells, caused changes in cell morphology[6].
In vivo, Amifostine treatment at a single dose of 200mg/kg for 18h attenuated lipopolysaccharide (LPS)-induced lung vascular leak and inhibited neutrophil accumulation in the lung parenchyma within mice[7]. A single subcutaneous injection of Amifostine (200mg/kg) for 30 minutes later significantly induced the expression of HIF1α in the tissues of normal rats[8].
References:
[1] Koukourakis M I. Amifostine in clinical oncology: current use and future applications[J]. Anti-cancer drugs, 2002, 13(3): 181-209.
[2] Van den Berg J H, Beijnen J H, Balm A J M, et al. Future opportunities in preventing cisplatin induced ototoxicity[J]. Cancer treatment reviews, 2006, 32(5): 390-397.
[3] Kalman N S, Zhao S S, Anscher M S, et al. Current status of targeted radioprotection and radiation injury mitigation and treatment agents: a critical review of the literature[J]. International Journal of Radiation Oncology* Biology* Physics, 2017, 98(3): 662-682.
[4] Ribizzi I, Darnowski J W, Goulette F A, et al. Amifostine cytotoxicity and induction of apoptosis in a human myelodysplastic cell line[J]. Leukemia research, 2000, 24(6): 519-525.
[5] Romano M F, Lamberti A, Bisogni R, et al. Amifostine inhibits hematopoietic progenitor cell apoptosis by activating NF-κB/Rel transcription factors[J]. Blood, The Journal of the American Society of Hematology, 1999, 94(12): 4060-4066.
[6] Wang H, Yang B, Hu B, et al. The effect of amifostine on differentiation of the human megakaryoblastic Dami cell line[J]. Cancer Medicine, 2016, 5(8): 2012-2021.
[7] Fu P, Birukova A A, Xing J, et al. Amifostine reduces lung vascular permeability via suppression of inflammatory signalling[J]. European Respiratory Journal, 2009, 33(3): 612-624.
[8] Koukourakis M I, Giatromanolaki A, Chong W, et al. Amifostine induces anaerobic metabolism and hypoxia-inducible factor 1α[J]. Cancer chemotherapy and pharmacology, 2004, 53(1): 8-14.
Amifostine是一种有机硫代磷酸盐，属于选择性广谱正常组织细胞保护剂[1]。Amifostine在体内经碱性磷酸酶去磷酸化后形成活性代谢物WR-1065，可清除氧自由基并增强DNA修复过程[2]。Amifostine已广泛应用于减轻放射治疗引起的急性口腔黏膜炎严重程度[3]。
在体外，Amifostine处理5天能显著抑制骨髓增生异常综合征(MDS)细胞增殖，IC50值为14μM[4]。使用100μg/ml的Amifostine处理32D细胞12小时，可抑制细胞凋亡并提高细胞核内NF-κB/Rel水平[5]。当浓度为1mM时，Amifostine处理12天能显著抑制Dami细胞增殖并引起细胞形态改变[6]。
在体内，单次注射200mg/kg剂量的Amifostine 18小时后，可减轻脂多糖(LPS)诱导的小鼠肺血管渗漏，并抑制肺实质中性粒细胞聚集[7]。单次皮下注射200mg/kg剂量的Amifostine 30分钟，能显著诱导正常大鼠组织中HIF1α的表达[8]。