Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium 168555-66-6

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Molecular Weight: 440.29 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. Fosbretabulin Disodium inhibits the polymerization of tubulin with IC50 of 2.4 μM, and also disrupts tumor vasculature. Phase 3.


Biological Activity


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. CA4 is cytotoxic towards proliferating but not quiescent
endothelial cells, has potent and selective toxicity towards tumor
vasculature. 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. 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.


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. CA4P(100 mg/kg, 6
h following administration) reduces tumor blood by approximately
100-fold, compared with approximately 7-fold in the spleen.


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 (

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.
Solubility	Saline with a few drops of 5% Na2CO3 , 30 mg/mL
* 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.

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

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

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)

Chemical Information

Molecular Weight (MW)	440.29
Formula	C18H19O8P.2Na
CAS No.	168555-66-6

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	<1 mg/mL (
		Water	28 mg/mL (63.59 mM)
		Ethanol	<1 mg/mL (
	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)

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Product Categories : Cytoskeletal Signaling > Microtubule Associated Inhibitor