Fosbretabulin (Combretastatin A4 Phosphate) Disodium

Catalog No.S7204 Batch:S720401

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Technical Data

Formula

C18H19O8P.2Na
Molecular Weight 440.29 CAS No. 168555-66-6
Solubility (25°C)* In vitro Water 28 mg/mL (63.59 mM)
DMSO Insoluble
Ethanol Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description 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.
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 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 Best for advanced solid tumors, anaplastic thyroid cancer, & choroidal neovascularization.

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 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

  • Dosages

    100 mg/kg, 3 ml/kg

  • Administration

    i.p.

References

  • https://pubmed.ncbi.nlm.nih.gov/7710932/
  • https://pubmed.ncbi.nlm.nih.gov/9157969/
  • https://pubmed.ncbi.nlm.nih.gov/11877280/
  • https://pubmed.ncbi.nlm.nih.gov/16224539/
  • https://pubmed.ncbi.nlm.nih.gov/10197639/

Customer Product Validation

Real-time hemodynamic changes in the tumor upon administration of CA4P. Panel A shows the MRI anatomical reference of the tumor, followed by sO2 maps of a slice of brain showing the largest cross section of the tumor at time points 0, 1, 4 and 6 h. post CA4P administration. Panel B shows the real-time sO2 changes in the tumor and contralateral brain occurring immediately post CA4P administration over 1 hour in a representative animal. SD is represented by lighter shades on the graph. Panel C shows the real-time sO2 changes in the tumor and contralateral brain occurring immediately post CA4P administration (n = 4). Panel D shows the quantification of hypoxia in tumors using CAIX as a marker at times 0 (n = 3), 1 (n = 4) and 6 h. (n = 3) post CA4P administration. Unpaired t-test showed statistically significant difference in CAIX staining at 1 hour post CA4P administration compared to 0 and 6 hours. ** ‐ P > 0.01. Black dotted circle and Red full circle denote the ROIs drawn at the tumor and contralateral brain respectively to compute the sO2.

Data from [ , , Transl Oncol, 2018, 11(5):1251-1258 ]

Immunofluorescence analysis of the effects of CA4P on NECs using confocal microscopy. The effects of CA4P (100 nM) on tubulin (pseudo-color green) and actin (pseudo-color red) were evaluated in subconfluent and 100% confluent NECs. Nuclei are shown in pseudo-color blue. CA4P (100 nM) disrupted tubulin on both subconfluent and 100% confluent NECs in a time-dependent manner. In subconfluent NECs, cell morphology was gradually changed from a spindle shape to a round shape, and actin reorganization was observed by adding 100 nM CA4P for 3 h. However, CA4P did not affect cell morphology or actin in 100% confluent NECs. Scale bar = 20 μm. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Data from [ , , Res Vet Sci, 2017, 112:222-228 ]

Representative images of Dylight 488-tomato lectin (pseudo-colored green) and Alexa-fluor 555-CD31 (pseudo-colored red) immuno-stained frozen sections from xenografted canine osteosarcoma tumors in the different treatment groups: control; combretastatin A-4 phosphate (CA4P, 30 mg/kg); VE-cadherin neutralizing antibody (VEC NAb, 40 μg/mouse); combination treatment (30 mg/kg CA4P 21 h after 40 μg VEC NAb); and CA4P (100 mg/kg). The upper half of this figure shows the image of the whole tumor and the lower half shows a magnified image. Tumors were excised 3 h after CA4P treatment or 24 h after VEC NAb treatment. Scale bars represent 1 mm or 100 μm.

Data from [ , , Res Vet Sci, 2018, 122:1-6 ]

Selleck's Fosbretabulin (Combretastatin A4 Phosphate) Disodium has been cited by 14 publications

PI3K/AKT signaling mediates stress-inducible amyloid formation through c-Myc [ Cell Rep, 2025, 44(5):115617] PubMed: 40272983
Antitumor effect of anti-vascular therapy with STING agonist depends on the tumor microenvironment context [ Front Oncol, 2023, 13:1249524] PubMed: 37655095
Antitumor effect of anti-vascular therapy with STING agonist depends on the tumor microenvironment context [ Front Oncol, 2023, 13:1249524] PubMed: 37655095
The Global Phosphorylation Landscape of SARS-CoV-2 Infection [ Cell, 2020, 182(3):685-712.e19] PubMed: 32645325
The Global Phosphorylation Landscape of SARS-CoV-2 Infection [ Cell, 2020, 182(3):685-712.e19] PubMed: 32645325
Salmonella enterica Typhimurium engineered for nontoxic systemic colonization of autochthonous tumors [ J Drug Target, 2020, 10.1080/1061186X.2020.1818759] PubMed: 32886538
Power Doppler ultrasound and contrast-enhanced ultrasound demonstrate non-invasive tumour vascular response to anti-vascular therapy in canine cancer patients [ Sci Rep, 2019, 9(1):9262] PubMed: 31239493
Noninvasive Anatomical and Functional Imaging of Orthotopic Glioblastoma Development and Therapy using Multispectral Optoacoustic Tomography [Balasundaram G, et al. Transl Oncol, 2018, 11(5):1251-1258] PubMed: 30103155
7α,8α-Epoxynagilactones and their glucosides from the twigs of Podocarpus nagi: Isolation, structures, and cytotoxic activities [ Fitoterapia, 2018, 125:174-183] PubMed: 29355751
Vascular disrupting effect of combretastatin A-4 phosphate with inhibition of vascular endothelial cadherin in canine osteosarcoma-xenografted mice [Izumi Y, et al. Res Vet Sci, 2018, 122:1-6] PubMed: 30439557

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