Fosbretabulin disodium - CAS 168555-66-6
Catalog number: 168555-66-6
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C18H19Na2O8P
Molecular Weight:
440.295
COA:
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Targets:
Microtubule/Tubulin
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.
Synonyms:
Combretastatin A-4 phosphate disodium, CA4P; CA4DP; Combretastatin A-4 phosphate
MSDS:
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InChIKey:
VXNQMUVMEIGUJW-XNOMRPDFSA-L
InChI:
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-;;
Canonical SMILES:
COC1=C(C=C(C=C1)C=CC2=CC(=C(C(=C2)OC)OC)OC)OP(=O)([O-])[O-].[Na+].[Na+]
Current Developer:
white solid powder
1.Treatment with a vascular disrupting agent does not increase recruitment of indium labelled human endothelial outgrowth cells in an experimental tumour model.
Bertelsen LB1, Bohn AB, Shen YY, Falborg L, Stødkilde-Jørgensen H, Horsman MR. BMC Cancer. 2014 Dec 2;14:903. doi: 10.1186/1471-2407-14-903.
BACKGROUND: The effect of vascular disrupting agents in tumour therapy depends on both the immediate vascular shutdown, and on the following re-vascularization of the tumour. The aim of this study was to use a tumour model to investigate whether endothelial outgrowth cells (EOCs) influenced the short term treatment efficiency of combretastatin A-4 disodium phosphate (CA4P) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by increasing EOC tumour recruitment.
2.Early effects of combretastatin-A4 disodium phosphate on tumor perfusion and interstitial fluid pressure.
Ley CD1, Horsman MR, Kristjansen PE. Neoplasia. 2007 Feb;9(2):108-12.
Combretastatin-A4 disodium phosphate (CA4DP) is a vascular-disruptive agent that causes an abrupt decrease in tumor blood flow. The direct actions of CA4DP include increases in vascular permeability and destabilization of the endothelial cytoskeleton, which are thought to contribute to occlusion of the tumor vasculature. It has been proposed that increased permeability causes a transient increase in interstitial fluid pressure (IFP), which in turn could collapse intratumoral blood vessels. We examined the immediate effects of CA4DP on tumor IFP in C3H mammary carcinoma. Mice were treated with 100 mg/kg CA4DP by intraperitoneal injection. Tumor perfusion was recorded by laser Doppler flowmetry at separate time points, and IFP was recorded continuously by the wick-in-needle method. In this study, we found that CA4DP treatment resulted in a rapid reduction in tumor perfusion, followed by a decrease in IFP; no increases in IFP were observed.
3.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.
Breidahl T1, Nielsen FU, Stødkilde-Jørgensen H, Maxwell RJ, Horsman MR. Acta Oncol. 2006;45(3):306-16.
The aim of this study was to use magnetic resonance (MR) techniques to non-invasively compare the effects of the three leading vascular disrupting agents, namely combretastatin A-4 disodium phosphate (CA4DP), 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and ZD6126. A C3H mouse mammary carcinoma grown in the right rear foot of female CDF1 mice was used and treatments performed when tumours had reached 200 mm3 in volume. Drugs were prepared fresh before each experiment and intraperitoneally injected into restrained non-anaesthetised mice. Tumour response was evaluated using 31P-MR spectroscopy and T1- and T2- weighted imaging with a 7-Tesla, horizontal bore magnet, before and up to 24 hours after treatment. All three drugs significantly decreased bioenergetic status and pH, and did so in a time and dose dependent fashion, but there were differences; the decrease by CA4DP occurred more rapidly than for DMXAA or ZD6126, while DMXAA had a narrow window of activity compared to CA4DP and ZD6126.
4.Tumour vascular disrupting agents: combating treatment resistance.
Tozer GM1, Kanthou C, Lewis G, Prise VE, Vojnovic B, Hill SA. Br J Radiol. 2008 Oct;81 Spec No 1:S12-20. doi: 10.1259/bjr/36205483.
A large group of tubulin-binding microtubule-depolymerizing agents act as tumour vascular disrupting agents (VDAs). Several members of this group are now in clinical trials in combination with conventional anticancer drugs and radiotherapy. Here we briefly update on the development of tubulin-binding combretastatins as VDAs, summarize what is known of their mechanisms of action and address issues relating to treatment resistance, using disodium combretastatin A-4 3-O-phosphate (CA-4-P) as an example. Characteristically, VDAs cause a rapid shutdown of blood flow to tumour tissue with much less effect in normal tissues. However, the tumour rim is relatively resistant to treatment. Hypoxia (or hypoxia reoxygenation) induces upregulation of genes associated with angiogenesis and drug resistance. It may be possible to take advantage of treatment-induced hypoxia by combining with drugs that are activated under hypoxic conditions. In summary, VDAs provide a novel approach to cancer treatment, which should effectively complement standard treatments, if treatment resistance is addressed by judicious combination treatment strategies.
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CAS 168555-66-6 Fosbretabulin disodium

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