WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H200800
CAS#: 168555-66-6 (disodium)
Description: 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.
Hodoodo Cat#: H200800
Name: Fosbretabulin disodium
CAS#: 168555-66-6 (disodium)
Chemical Formula: C18H19Na2O8P
Exact Mass: 0.00
Molecular Weight: 440.290
Elemental Analysis: C, 49.10; H, 4.35; Na, 10.44; O, 29.07; P, 7.03
Related CAS #: 168555-66-6 (disodium) 222030-63-9 (free acid) 404886-32-4 ( tromethamine),
Synonym: Combretastatin A4 phosphate disodium; CA4P; CA4DP; Combretastatin A4 phosphate; Fosbretabulin disodium; Zybrestat
IUPAC/Chemical Name: Disodium [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] phosphate
InChi Key: VXNQMUVMEIGUJW-XNOMRPDFSA-L
InChi Code: InChI=1S/C18H21O8P.2Na/c1-22-14-8-7-12(9-15(14)26-27(19,20)21)5-6-13-10-16(23-2)18(25-4)17(11-13)24-3;;/h5-11H,1-4H3,(H2,19,20,21);;/q;2*+1/p-2/b6-5-;;
SMILES Code: O=P([O-])([O-])OC1=CC(/C=C\C2=CC(OC)=C(OC)C(OC)=C2)=CC=C1OC.[Na+].[Na+]
Appearance: white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info: Related CAS# 168555-66-6 (fosbretabulin disodium); 222030-63-9 (fosbretabulin); 82855-09-2 (combretastatin); 117048 -59-6 (combretastatin A4)
Biological target: | Fosbretabulin disodium is a tubulin destabilizing agent that selectively targets endothelial cells. |
In vitro activity: | The present observations reveal a novel effect of CA4P, i.e. the triggering of suicidal erythrocyte death or eryptosis. Exposure of human erythrocytes to CA4P results in cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. The CA4P concentrations required for the stimulation of eryptosis are in the range of concentrations encountered in the plasma of patients. The higher concentrations employed here (50 and 100 µM) would be approached, however, only following intake of toxic drug doses. Reference: Cell Physiol Biochem. 2016; 38(3): 969-81. https://air.unimi.it/handle/2434/391841#.YK_V9ahKiUk |
In vivo activity: | At 0.5 h after dosing, decreases in HR, EF, and CO and increases in plasma CK, CK-MB, and FABP3 were detected in CA4DP (Fosbretabulin disodium)-treated rats. Meanwhile, slight histopathological changes in the myocardium and capillary were observed, but changes in HR and EF were not obvious at 24 h after dosing. At 72 h after dosing, severe histopathological changes in the myocardium were observed, and decreases in HR, EF, and CO recurred. These results suggested that CA4DP-induced cardiac events in rats had occurred within a few minutes and recovered temporarily at 24 h along with the decreases in blood level of CA4DP. Progression of necrosis and inflammation in addition to deterioration of general condition might induce decreases in HR, EF, and CO again. Reference: J Toxicol Pathol. 2018 Oct; 31(4): 307–313. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206283/ |
Solvent | Max Conc. mg/mL | Max Conc. mM | |
---|---|---|---|
Solubility | |||
DMF | 1.0 | 2.27 | |
PBS (pH 7.2) | 5.0 | 11.36 | |
Water | 4.5 | 10.22 |
The following data is based on the product molecular weight 440.29 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
---|---|---|---|
1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
Formulation protocol: | 1. Signoretto E, Bissinger R, Castagna M, Lang F. Stimulation of Eryptosis by Combretastatin A4 Phosphate Disodium (CA4P). Cell Physiol Biochem. 2016;38(3):969-81. doi: 10.1159/000443049. Epub 2016 Mar 4. PMID: 26938611. 2. Tochinai R, Komatsu K, Murakami J, Nagata Y, Ando M, Hata C, Suzuki T, Kado S, Kobayashi T, Kuwahara M. Histopathological and functional changes in a single-dose model of combretastatin A4 disodium phosphate-induced myocardial damage in rats. J Toxicol Pathol. 2018 Oct;31(4):307-313. doi: 10.1293/tox.2018-0023. Epub 2018 Aug 5. PMID: 30393435; PMCID: PMC6206283. 2. Ley CD, Horsman MR, Kristjansen PE. Early effects of combretastatin-A4 disodium phosphate on tumor perfusion and interstitial fluid pressure. Neoplasia. 2007 Feb;9(2):108-1 3. doi: 10.1593/neo.06733. PMID: 17356706; PMCID: PMC1813937. |
In vitro protocol: | Signoretto E, Bissinger R, Castagna M, Lang F. Stimulation of Eryptosis by Combretastatin A4 Phosphate Disodium (CA4P). Cell Physiol Biochem. 2016;38(3):969-81. doi: 10.1159/000443049. Epub 2016 Mar 4. PMID: 26938611. |
In vivo protocol: | 1. Tochinai R, Komatsu K, Murakami J, Nagata Y, Ando M, Hata C, Suzuki T, Kado S, Kobayashi T, Kuwahara M. Histopathological and functional changes in a single-dose model of combretastatin A4 disodium phosphate-induced myocardial damage in rats. J Toxicol Pathol. 2018 Oct;31(4):307-313. doi: 10.1293/tox.2018-0023. Epub 2018 Aug 5. PMID: 30393435; PMCID: PMC6206283. 2. Ley CD, Horsman MR, Kristjansen PE. Early effects of combretastatin-A4 disodium phosphate on tumor perfusion and interstitial fluid pressure. Neoplasia. 2007 Feb;9(2):108-12. doi: 10.1593/neo.06733. PMID: 17356706; PMCID: PMC1813937. |
1: Sosa JA, Balkissoon J, Lu SP, Langecker P, Elisei R, Jarzab B, Bal CS, Marur S, Gramza A, Ondrey F. Thyroidectomy followed by fosbretabulin (CA4P) combination regimen appears to suggest improvement in patient survival in anaplastic thyroid cancer. Surgery. 2012 Dec;152(6):1078-87. doi: 10.1016/j.surg.2012.08.036. Review. PubMed PMID: 23158178.
2: Venegas B, Zhu W, Haloupek NB, Lee J, Zellhart E, Sugár IP, Kiani MF, Chong PL. Cholesterol superlattice modulates CA4P release from liposomes and CA4P cytotoxicity on mammary cancer cells. Biophys J. 2012 May 2;102(9):2086-94. doi: 10.1016/j.bpj.2012.03.063. PubMed PMID: 22824272; PubMed Central PMCID: PMC3341537.
3: Nathan P, Zweifel M, Padhani AR, Koh DM, Ng M, Collins DJ, Harris A, Carden C, Smythe J, Fisher N, Taylor NJ, Stirling JJ, Lu SP, Leach MO, Rustin GJ, Judson I. Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer. Clin Cancer Res. 2012 Jun 15;18(12):3428-39. doi: 10.1158/1078-0432.CCR-11-3376. Epub 2012 May 29. PubMed PMID: 22645052.
4: 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. doi: 10.1038/sj.bjc.6605650. Epub 2010 Apr 13. PubMed PMID: 20389300; PubMed Central PMCID: PMC2865759.
5: Siemann DW, Chaplin DJ, Walicke PA. A review and update of the current status of the vasculature-disabling agent combretastatin-A4 phosphate (CA4P). Expert Opin Investig Drugs. 2009 Feb;18(2):189-97. doi: 10.1517/13543780802691068 . Review. PubMed PMID: 19236265; PubMed Central PMCID: PMC3593193.
6: Siemann DW, Shi W. Dual targeting of tumor vasculature: combining Avastin and vascular disrupting agents (CA4P or OXi4503). Anticancer Res. 2008 Jul-Aug;28(4B):2027-31. PubMed PMID: 18751370; PubMed Central PMCID: PMC2788501.
7: Petit I, Karajannis MA, Vincent L, Young L, Butler J, Hooper AT, Shido K, Steller H, Chaplin DJ, Feldman E, Rafii S. The microtubule-targeting agent CA4P regresses leukemic xenografts by disrupting interaction with vascular cells and mitochondrial-dependent cell death. Blood. 2008 Feb 15;111(4):1951-61. Epub 2007 Nov 16. PubMed PMID: 18024794; PubMed Central PMCID: PMC2234044.
8: Salmon BA, Salmon HW, Siemann DW. Monitoring the treatment efficacy of the vascular disrupting agent CA4P. Eur J Cancer. 2007 Jul;43(10):1622-9. Epub 2007 Apr 23. PubMed PMID: 17451938; PubMed Central PMCID: PMC2962830.
9: Salmon HW, Mladinich C, Siemann DW. Evaluations of vascular disrupting agents CA4P and OXi4503 in renal cell carcinoma (Caki-1) using a silicon based microvascular casting technique. Eur J Cancer. 2006 Nov;42(17):3073-8. Epub 2006 Sep 7. PubMed PMID: 16956760.