Back to products

Browse products

MedKoo product information:

 Fosbretabulin disodium

Description of Fosbretabulin disodium: Fosbretabulin disodium is the disodium salt of a water-soluble phosphate derivative of a natural stilbenoid phenol derived from the African bush willow (Combretum caffrum) with potential vascular disrupting and antineoplastic activities. Upon administration, the prodrug fosbretabulin is dephosphorylated to its active metabolite, the microtubule-depolymerizing agent combretastatin A4, which binds to tubulin dimers and prevents microtubule polymerization, resulting in mitotic arrest and apoptosis in endothelial cells. In addition, this agent disrupts the engagement of the endothelial cell–specific junctional molecule vascular endothelial-cadherin (VE-cadherin) and so the activity of the VE-cadherin/β-catenin/Akt signaling pathway, which may result in the inhibition of endothelial cell migration and capillary tube formation. As a result of fosbretabulin's dual mechanism of action, the tumor vasculature collapses, resulting in reduced tumor blood flow and ischemic necrosis of tumor tissue. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   OXiGENE, Inc.

1: Rustin GJ, Shreeves G, Nathan PD, Gaya A, Ganesan TS, Wang D, Boxall J, Poupard L, Chaplin DJ, Stratford MR, Balkissoon J, Zweifel M. A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer. Br J Cancer. 2010 Apr 27;102(9):1355-60. Epub 2010 Apr 13. PubMed PMID: 20389300.

2: Zhu H, Zhang J, Xue N, Hu Y, Yang B, He Q. Novel combretastatin A-4 derivative XN0502 induces cell cycle arrest and apoptosis in A549 cells. Invest New Drugs. 2010 Aug;28(4):493-501. Epub 2010 Mar 30. PubMed PMID: 20352291.

3: Coccetti P, Montano G, Lombardo A, Tripodi F, Orsini F, Pagliarin R. Synthesis and biological evaluation of combretastatin analogs as cell cycle inhibitors of the G1 to S transition in Saccharomyces cerevisiae. Bioorg Med Chem Lett. 2010 May 1;20(9):2780-4. Epub 2010 Mar 17. PubMed PMID: 20363626.

4: Zhang YF, Wang JC, Bian DY, Zhang X, Zhang Q. Targeted delivery of RGD-modified liposomes encapsulating both combretastatin A-4 and doxorubicin for  tumor therapy: in vitro and in vivo studies. Eur J Pharm Biopharm. 2010 Mar;74(3):467-73. Epub 2010 Jan 11. PubMed PMID: 20064608.

5: Pettit GR, Minardi MD, Hogan F, Price PM. An efficient synthetic strategy for  obtaining 4-methoxy carbon isotope labeled combretastatin A-4 phosphate and other Z-combretastatins. J Nat Prod. 2010 Mar 26;73(3):399-403. PubMed PMID: 20028026;  PubMed Central PMCID: PMC2862752.

6: Ke Q, Bodyak N, Rigor DL, Hurst NW, Chaplin DJ, Kang PM. Pharmacological inhibition of the hypertensive response to combretastatin A-4 phosphate in rats.  Vascul Pharmacol. 2009 Nov-Dec;51(5-6):337-43. Epub 2009 Sep 6. PubMed PMID: 19737629.

7: Tozer GM, Prise VE, Lewis G, Xie S, Wilson I, Hill SA. Nitric oxide synthase inhibition enhances the tumor vascular-damaging effects of combretastatin a-4 3-o-phosphate at clinically relevant doses. Clin Cancer Res. 2009 Jun 1;15(11):3781-90. Epub 2009 May 26. PubMed PMID: 19470729.

8: Aprile S, Del Grosso E, Grosa G. In vitro and in vivo phase II metabolism of combretastatin A-4: evidence for the formation of a sulphate conjugate metabolite. Xenobiotica. 2009 Feb;39(2):148-61. PubMed PMID: 19255941.

9: Samarin J, Rehm M, Krueger B, Waschke J, Goppelt-Struebe M. Up-regulation of connective tissue growth factor in endothelial cells by the microtubule-destabilizing agent combretastatin A-4. Mol Cancer Res. 2009 Feb;7(2):180-8. Epub 2009 Feb 10. PubMed PMID: 19208742.

10: Zhang F, Sun C, Wu J, He C, Ge X, Huang W, Zou Y, Chen X, Qi W, Zhai Q. Combretastatin A-4 activates AMP-activated protein kinase and improves glucose metabolism in db/db mice. Pharmacol Res. 2008 Apr;57(4):318-23. Epub 2008 Mar 15. PubMed PMID: 18434188.

11: James C, Pettit GR, Nielsen OF, Jayakumar VS, Joe IH. Vibrational spectra and ab initio molecular orbital calculations of the novel anti-cancer drug combretastatin A-4 prodrug. Spectrochim Acta A Mol Biomol Spectrosc. 2008 Oct;70(5):1208-16. Epub 2007 Nov 21. PubMed PMID: 18248845.

12: Chaudhary A, Pandeya SN, Kumar P, Sharma PP, Gupta S, Soni N, Verma KK, Bhardwaj G. Combretastatin a-4 analogs as anticancer agents. Mini Rev Med Chem. 2007 Dec;7(12):1186-205. Review. PubMed PMID: 18220974.

13: Nielsen T, Murata R, Maxwell RJ, Stødkilde-Jørgensen H, Ostergaard L, Horsman MR. Preclinical studies to predict efficacy of vascular changes induced by combretastatin a-4 disodium phosphate in patients. Int J Radiat Oncol Biol Phys.  2008 Mar 1;70(3):859-66. Epub 2007 Dec 31. PubMed PMID: 18164835.

14: Aprile S, Del Grosso E, Tron GC, Grosa G. In vitro metabolism study of combretastatin A-4 in rat and human liver microsomes. Drug Metab Dispos. 2007 Dec;35(12):2252-61. Epub 2007 Sep 21. PubMed PMID: 17890446.

15: Kador PF, Blessing K, Randazzo J, Makita J, Wyman M. Evaluation of the vascular targeting agent combretastatin a-4 prodrug on retinal neovascularization in the galactose-fed dog. J Ocul Pharmacol Ther. 2007 Apr;23(2):132-42. PubMed PMID: 17444801.

16: Salmon BA, Siemann DW. Characterizing the tumor response to treatment with combretastatin A4 phosphate. Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):211-7. PubMed PMID: 17448875; PubMed Central PMCID: PMC1868579.

17: Lankester KJ, Maxwell RJ, Pedley RB, Dearling JL, Qureshi UA, El-Emir E, Hill SA, Tozer GM. Combretastatin A-4-phosphate effectively increases tumor retention  of the therapeutic antibody, 131I-A5B7, even at doses that are sub-optimal for vascular shut-down. Int J Oncol. 2007 Feb;30(2):453-60. PubMed PMID: 17203228.

18: Dachs GU, Steele AJ, Coralli C, Kanthou C, Brooks AC, Gunningham SP, Currie MJ, Watson AI, Robinson BA, Tozer GM. Anti-vascular agent Combretastatin A-4-P modulates hypoxia inducible factor-1 and gene expression. BMC Cancer. 2006 Dec 7;6:280. PubMed PMID: 17156434; PubMed Central PMCID: PMC1702548.

19: Breidahl T, Nielsen FU, Stødkilde-Jørgensen H, Maxwell RJ, Horsman MR. The effects of the vascular disrupting agents combretastatin A-4 disodium phosphate,  5,6-dimethylxanthenone-4-acetic acid and ZD6126 in a murine tumour: a comparative assessment using MRI and MRS. Acta Oncol. 2006;45(3):306-16. PubMed PMID: 16644574.

20: Ahmed B, Landuyt W, Griffioen AW, Van Oosterom A, Van den Bogaert W, Lambin P. In vivo antitumour effect of combretastatin A-4 phosphate added to fractionated irradiation. Anticancer Res. 2006 Jan-Feb;26(1A):307-10. PubMed PMID: 16475711.

21: Wehbe H, Kearney CM, Pinney KG. Combretastatin A-4 resistance in H460 human lung carcinoma demonstrates distinctive alterations in beta-tubulin isotype expression. Anticancer Res. 2005 Nov-Dec;25(6B):3865-70. PubMed PMID: 16309172.

22: Thoeny HC, De Keyzer F, Chen F, Vandecaveye V, Verbeken EK, Ahmed B, Sun X, Ni Y, Bosmans H, Hermans R, van Oosterom A, Marchal G, Landuyt W. Diffusion-weighted magnetic resonance imaging allows noninvasive in vivo monitoring of the effects of combretastatin a-4 phosphate after repeated administration. Neoplasia. 2005 Aug;7(8):779-87. PubMed PMID: 16207480; PubMed Central PMCID: PMC1501887.

23: El-Emir E, Boxer GM, Petrie IA, Boden RW, Dearling JL, Begent RH, Pedley RB.  Tumour parameters affected by combretastatin A-4 phosphate therapy in a human colorectal xenograft model in nude mice. Eur J Cancer. 2005 Mar;41(5):799-806. PubMed PMID: 15763657.

24: Bilenker JH, Flaherty KT, Rosen M, Davis L, Gallagher M, Stevenson JP, Sun W, Vaughn D, Giantonio B, Zimmer R, Schnall M, O'Dwyer PJ. Phase I trial of combretastatin a-4 phosphate with carboplatin. Clin Cancer Res. 2005 Feb 15;11(4):1527-33. PubMed PMID: 15746056.

25: Escalona-Benz E, Jockovich ME, Murray TG, Hayden B, Hernandez E, Feuer W, Windle JJ. Combretastatin A-4 prodrug in the treatment of a murine model of retinoblastoma. Invest Ophthalmol Vis Sci. 2005 Jan;46(1):8-11. PubMed PMID: 15623747.

26: Kanthou C, Greco O, Stratford A, Cook I, Knight R, Benzakour O, Tozer G. The  tubulin-binding agent combretastatin A-4-phosphate arrests endothelial cells in mitosis and induces mitotic cell death. Am J Pathol. 2004 Oct;165(4):1401-11. PubMed PMID: 15466404.

27: West CM, Price P. Combretastatin A4 phosphate. Anticancer Drugs. 2004 Mar;15(3):179-87. Review. PubMed PMID: 15014350.

28: Wildiers H, Ahmed B, Guetens G, De Boeck G, de Bruijn EA, Landuyt W, van Oosterom AT. Combretastatin A-4 phosphate enhances CPT-11 activity independently  of the administration sequence. Eur J Cancer. 2004 Jan;40(2):284-90. PubMed PMID: 14728944.

29: Cirla A, Mann J. Combretastatins: from natural products to drug discovery. Nat Prod Rep. 2003 Dec;20(6):558-64. Review. PubMed PMID: 14700199.

30: Stevenson JP, Rosen M, Sun W, Gallagher M, Haller DG, Vaughn D, Giantonio B,  Zimmer R, Petros WP, Stratford M, Chaplin D, Young SL, Schnall M, O'Dwyer PJ. Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow. J Clin Oncol. 2003 Dec 1;21(23):4428-38. PubMed PMID: 14645433.