Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium

Catalog No.S7204

Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) 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. Phase 3.

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

Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium Chemical Structure
Molecular Weight: 440.29

Validation & Quality Control

Quality Control & MSDS

Product Information

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Product Description

Biological Activity

Description Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) 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. Phase 3.
Targets Tubulin [1]
(Cell-free assay)
IC50 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]
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]
Features A microtubule associated inhibitor with higher affinity to β-tubulin vs. Colchicine. Best for advanced solid tumors, anaplastic thyroid cancer, & choroidal neovascularization.

Protocol(Only for 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 Assay:

[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 Study:

[5]

Animal Models BD9 rats implanted with tumor
Formulation 0.9% saline with a few drops of 5% Na2CO3
Dosages 100 mg/kg, 3 ml/kg
Administration i.p.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Woods JA, et al. Br J Cancer 1995, 71(4), 705-711.

[2] Dark GG, et al. Cancer Res 1997, 57(10), 1829-1834.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02641639 Recruiting Platinum Resistant Ovarian Cancer Mateon Therapeutics June 2016 Phase 2|Phase 3
NCT01701349 Withdrawn Anaplastic Thyroid Cancer Mateon Therapeutics March 2015 Phase 3
NCT02279602 Enrolling by invitation Neuroendocrine Tumors Mateon Therapeutics December 2014 Phase 2
NCT02055690 Recruiting Ovarian Neoplasms|Neoplasms, Ovarian|Ovarian Cancer Heather Driscoll|Novartis|Mateon Therapeutics|East and No  ...more Heather Driscoll|Novartis|Mateon Therapeutics|East and North Hertfordshire NHS Trust|The Christie NHS Foundation Trust September 2014 Phase 1|Phase 2
NCT02132468 Active, not recruiting Neuroendocrine Tumors Mateon Therapeutics September 2014 Phase 2

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Chemical Information

Download Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium SDF
Molecular Weight (MW) 440.29
Formula

C18H19O8P.2Na

CAS No. 168555-66-6
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro Water 28 mg/mL (63.59 mM)
DMSO <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo Saline with a few drops of 5% Na2CO3 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name Phenol, 2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]-, 1-(dihydrogen phosphate), sodium salt (1:2)

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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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