Home Cytoskeletal Signaling Microtubule Associated inhibitor Fosbretabulin (Combretastatin A4 Phosphate) Disodium

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Fosbretabulin (Combretastatin A4 Phosphate) Disodium Microtubule Associated inhibitor

Cat.No.S7204

Fosbretabulin (Combretastatin A4 Phosphate) 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) Disodium Microtubule Associated inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 440.29

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Quality Control

Batch: Purity: 99.86%
99.86

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
SKOV3 cells Proliferation assay Antiproliferative activity against human SKOV3 cells by sulforhodamine B assay, IC50=0.0045 μM
HeLa cells Proliferation assay Antiproliferative activity against human HeLa cells by sulforhodamine B assay, IC50=0.0047 μM
rat A10 cells Function assay Inhibition of microtubule depolymerization in rat A10 cells assessed as reorganization of interphase microtubule network by indirect immunofluorescence technique, EC50=0.007 μM
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Solubility

In vitro
Batch:

Water : 28 mg/mL

DMSO : Insoluble
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : Insoluble

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In vivo
Batch:

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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.

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Chemical Information, Storage & Stability

Molecular Weight 440.29 Formula

C18H19O8P.2Na

 Storage (From the date of receipt)
CAS No. 168555-66-6 Download SDF Storage of Stock Solutions

Synonyms CA 4DP Smiles COC1=C(C=C(C=C1)C=CC2=CC(=C(C(=C2)OC)OC)OC)OP(=O)([O-])[O-].[Na+].[Na+]

Mechanism of Action

Features
Best for advanced solid tumors, anaplastic thyroid cancer, & choroidal neovascularization.
Targets/IC50/Ki
Tubulin
(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 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.

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

References
  • [4] https://pubmed.ncbi.nlm.nih.gov/16224539/
  • [5] https://pubmed.ncbi.nlm.nih.gov/10197639/

Applications

Methods Biomarkers Images PMID
Immunofluorescence tubulin / VE-cadherin Actin / N-cadherin / CD31
S7204-IF1
29221156

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02641639 Terminated
Platinum Resistant Ovarian Cancer
Mateon Therapeutics
 June 2016 Phase 2|Phase 3
NCT02055690 Terminated
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
Polypoidal Choroidal Vasculopathy
Mateon Therapeutics
 July 2009 Phase 2

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