Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium

Catalog No.S7204 Synonyms: CA 4DP

For research use only.

Fosbretabulin (Combretastatin A4 Phosphate, CA4P, CA 4DP) Disodium is the water-soluble prodrug of Combretastatin A4 (CA4), which is a microtubule-targeting agent that binds β-tubulin with Kd of 0.4 μM in a cell-free assay. Fosbretabulin Disodium inhibits the polymerization of tubulin with IC50 of 2.4 μM, and also disrupts tumor vasculature. Fosbretabulin disodium induces mitotic arrest and apoptosis in endothelial cells. Phase 3.

Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium Chemical Structure

CAS No. 168555-66-6

Selleck's Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium has been cited by 10 Publications

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Purity & Quality Control

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Biological Activity

Description Fosbretabulin (Combretastatin A4 Phosphate, CA4P, CA 4DP) Disodium is the water-soluble prodrug of Combretastatin A4 (CA4), which is a microtubule-targeting agent that binds β-tubulin with Kd of 0.4 μM in a cell-free assay. Fosbretabulin Disodium inhibits the polymerization of tubulin with IC50 of 2.4 μM, and also disrupts tumor vasculature. Fosbretabulin disodium induces mitotic arrest and apoptosis in endothelial cells. Phase 3.
Features A microtubule associated inhibitor with higher affinity to β-tubulin vs. Colchicine. Best for advanced solid tumors, anaplastic thyroid cancer, & choroidal neovascularization.
Targets
Tubulin [1]
(Cell-free assay)
2.4 μM
In vitro

Fosbretabulin disodium (Combretastatin A-4 phosphate disodium, CA4P disodium) is the water-soluble prodrug of combretastatin A4 (CA4), which is originally isolated from African tree Combretum caffrum. CA4 is a tubulin-binding agent that binds at or near the colchicine binding site of β-tubulin (Kd = 0.40 μM), inhibits tubulin assembly with IC50 of 2.4 μM. [1] CA4 is cytotoxic towards proliferating but not quiescent endothelial cells, has potent and selective toxicity towards tumor vasculature. [2] CA4P (1 mM, 30 minutes) disrupts the endothelial microtubule cytoskeleton and mediates changes in endothelial cell morphology. CA4P stimulates actin stress fiber formation and membrane blebbing and increases monolayer permeability via Rho/Rho-kinase. [3] CA4P increases endothelial cell permeability, while inhibiting endothelial cell migration and capillary tube formation predominantly through disruption of VE-cadherin/β-catenin/Akt signaling pathway, thereby leading to rapid vascular collapse and tumor necrosis. [4]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
SKOV3 cells NI\lO29Rem:uaX\ldoF1cW:wIHHzd4F6 MYjBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKFONT2[zJINmdGy|IHL5JJN2dG[xcnjv[IFucW6nIFKgZZN{[XluIFnDOVA:OC5yMES1JO69VQ>? MmDINlA6PzN2OEi=
HeLa cells NVrN[odUWHKxbHnm[ZJifGmxbjDhd5NigQ>? MX\BcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKEinTHGgZ4VtdHNiYomgd5Vt\m:{aH;kZY1qdmViQjDhd5NigSxiSVO1NF0xNjByNEeg{txO NVTtdXBFOjB7N{O0PFg>
rat A10 cells MnnFSpVv[3Srb36gZZN{[Xl? NULzfnZWUW6qaXLpeIlwdiCxZjDtbYNzd3S3YoXs[UBl\XCxbInt[ZJqgmG2aX;uJIlvKHKjdDDBNVAh[2WubIOgZZN{\XO|ZXSgZZMhemWxcnfhcol7[XSrb36gc4YhcW62ZYLwbIF{\SCvaXPyc5R2[nWuZTDu[ZR4d3KtIHL5JIlv\Gm{ZXP0JIludXWwb3\seY9z\XOlZX7j[UB1\WOqbnnxeYUtKEWFNUC9NE4xODdizszN NUHCfmppOjB7N{O0PFg>
Assay
Methods Test Index PMID
Immunofluorescence tubulin / VE-cadherin ; Actin / N-cadherin / CD31 29221156
In vivo CA4P causes rapid, extensive and irreversible vascular shutdown in experimental tumor models following the administration of a single dose at 10% of the maximum tolerated dose (MTD). CA4P causes a 93% reduction in vascular volume 6 h following drug administration. [2] CA4P(100 mg/kg, 6 h following administration) reduces tumor blood by approximately 100-fold, compared with approximately 7-fold in the spleen. [5]

Protocol (from reference)

Kinase Assay:

[1]

  • Tubulin assembly-disassembly:

    The assembly of microtubules from isolated tubulin is carried out spectrophotometrically at 350 nm and utilises the increase in turbidity which is associated with microtubule formation. Assembly is initiated by temperature increase from 10 to 35 °C. The effect of drugs on the increase in light absorption is carried. Drugs are dissolved in DMSO (<4%), which does not affect control assembly

Cell Research:

[4]

  • Cell lines: HUVECs
  • Concentrations: ~50 nM
  • Incubation Time: 12-48 h
  • Method:

    For the proliferation assay, the minimal concentration of FBS (1%) diluted in X-VIVO medium is used to allow sufficient viability of endothelial cells. After detachment, the cells are seeded at a concentration of 2×104 HUVECs in each well of 24-well plates, allowed to adhere overnight, and then incubated with or without cytokines (5 ng/ml FGF-2 or 5 ng/ml VEGF-A). CA4P is added at 0 – 50 nM. After incubation for 12, 24, 36, and 48 hours, cells are detached by trypsin/EDTA and manually counted using trypan blue exclusion.

Animal Research:

[5]

  • Animal Models: BD9 rats implanted with tumor
  • Dosages: 100 mg/kg, 3 ml/kg
  • Administration: i.p.

Solubility (25°C)

In vitro

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
Saline with a few drops of 5% Na2CO3
For best results, use promptly after mixing.

30 mg/mL

Chemical Information

Molecular Weight 440.29
Formula

C18H19O8P.2Na

CAS No. 168555-66-6
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles COC1=C(C=C(C=C1)C=CC2=CC(=C(C(=C2)OC)OC)OC)OP(=O)([O-])[O-].[Na+].[Na+]

In vivo Formulation Calculator (Clear solution)

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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02641639 Terminated Drug: Fosbretabulin tromethamine|Drug: Placebo Platinum Resistant Ovarian Cancer Mateon Therapeutics June 2016 Phase 2|Phase 3
NCT02055690 Terminated Drug: Pazopanib|Drug: Fosbretabulin Ovarian Neoplasms|Neoplasms Ovarian|Ovarian Cancer The Christie NHS Foundation Trust|Novartis|Mateon Therapeutics|East and North Hertfordshire NHS Trust September 2014 Phase 1|Phase 2
NCT01023295 Completed Drug: fosbretabulin|Drug: Saline Polypoidal Choroidal Vasculopathy Mateon Therapeutics July 2009 Phase 2

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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