Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium is a microtubule destabilizing drug, a water-soluble prodrug of combretasain A4(CA4) [1]. Fosbretabulin Disodium can be dephosphorylated in the body to form the active metabolite CA4, which promotes microtubule polymerization and thereby induces G2/M phase cell cycle arrest[2]. Fosbretabulin Disodium has been widely used to induce tumor necrosis and is employed as an adjuvant to develop new combined therapies[3].
In vitro, Fosbretabulin Disodium treatment for 48 hours significantly inhibited the proliferation of HepG2, Bel-7402, and MCF-7 cells, with IC50 values of 0.002μM, 0.04μM, and 0.011μM, respectively[4]. Fosbretabulin Disodium treatment at 1µM for 30min disrupted the microtubule skeleton of human umbilical vein endothelial cells (HUVECs) and altered cell morphology[5].
In vivo, Fosbretabulin Disodium treatment, administered by tail vein bolus (60mg/10ml/kg; 24h interval; four doses), resulted in multifocal necrosis, inflammatory cell infiltration, and telangiectasia in the myocardium of rats [6]. A single intraperitoneal injection of Fosbretabulin Disodium at a dose of 100mg/kg for 30min resulted in a rapid decrease in tumor perfusion followed by a subsequent decrease in interstitial fluid pressure in the C3H breast cancer mouse model[7]. A single intravenous injection of Fosbretabulin Disodium (10mg/kg) combined with low-dose γ-ray irradiation (0.20Gy; 0.685rad/sec) treatment for 24h inhibited N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma development in rats by down-regulating CD31 expression and gene expression of ROCK1 and VEGF[8].
References:
[1] Smolarczyk R, Czapla J, Jarosz-Biej M, et al. Vascular disrupting agents in cancer therapy[J]. European journal of pharmacology, 2021, 891: 173692.
[2] Lu Y, Chen J, Xiao M, et al. An overview of tubulin inhibitors that interact with the colchicine binding site[J]. Pharmaceutical research, 2012, 29(11): 2943-2971.
[3] Nagaiah G, Remick S C. Combretastatin A4 phosphate: a novel vascular disrupting agent[J]. Future Oncology, 2010, 6(8): 1219-1228.
[4] Liu Y, Wu Y, Gu Y, et al. Synthesis and structure-activity relationship study of water-soluble carbazole sulfonamide derivatives as new anticancer agents[J]. European journal of medicinal chemistry, 2020, 191: 112181.
[5] Kanthou C, Tozer G M. The tumor vascular targeting agent combretastatin A–4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells[J]. Blood, The Journal of the American Society of Hematology, 2002, 99(6): 2060-2069.
[6] Tochinai R, Nagata Y, Ando M, et al. Combretastatin A4 disodium phosphate-induced myocardial injury[J]. Journal of toxicologic pathology, 2016, 29(3): 163-171.
[7] Ley C D, Horsman M R, Kristjansen P E G. Early effects of combretastatin-A4 disodium phosphate on tumor perfusion and interstitial fluid pressure[J]. Neoplasia, 2007, 9(2): 108-112.
[8] Alghzzawy Z M, Elmaghraby T K, El-Hamid Hagag S A, et al. Combretastatin A-4 disodium phosphate and low dose gamma irradiation suppress hepatocellular carcinoma by downregulating ROCK1 and VEGF gene expression[J]. Molecular biology reports, 2020, 47(3): 1883-1893.
Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium是一种微管解聚药物，作为Combretastatin A4(CA4)的水溶性前体药物[1]。Fosbretabulin Disodium在体内经去磷酸化后可形成活性代谢物CA4，通过促进微管蛋白聚合诱导G2/M期细胞周期阻滞[2]。Fosbretabulin Disodium目前已广泛应用于诱导肿瘤坏死，并作为辅助物用于开发新型联合疗法[3]。
在体外，Fosbretabulin Disodium处理48小时能显著抑制HepG2、Bel-7402和MCF-7细胞增殖，IC50值分别为0.002μM、0.04μM和0.011 μM[4]。使用1µM的Fosbretabulin Disodium处理人脐静脉内皮细胞(HUVECs) 30分钟，可破坏微管骨架结构并改变细胞形态[5]。
在体内，通过尾静脉推注Fosbretabulin Disodium（60mg/10ml/kg; 24小时间隔给药; 给药4次）可导致大鼠心肌出现多灶性坏死、炎性细胞浸润及毛细血管扩张[6]。单次腹腔注射100mg/kg剂量的Fosbretabulin Disodium 30分钟，能迅速降低C3H乳腺癌小鼠模型的肿瘤灌注量，并随之降低组织间液压力[7]。单次静脉注射Fosbretabulin Disodium（10mg/kg）联合低剂量γ射线（0.20Gy; 0.685rad/sec）照射处理24小时，可通过下调CD31表达及ROCK1、VEGF基因表达，抑制N-nitrosodiethylamine (NDEA)诱导的大鼠肝细胞癌进展[8]。