Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium

Catalog No.S7204

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

Molecular Weight(MW): 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 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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Cited by 5 Publications

3 Customer Reviews

  • 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.

    Transl Oncol, 2018, 11(5):1251-1258. Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium purchased from Selleck.

    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.)

    Res Vet Sci, 2017, 112:222-228. Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium purchased from Selleck.

  • 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.

    Res Vet Sci, 2018, 122:1-6. Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium purchased from Selleck.

Purity & Quality Control

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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.
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 MkTFVJJwdGmoZYLheIlwdiCjc4PhfS=> NIXy[4JCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIGPLU3Y{KGOnbHzzJIJ6KHO3bH\vdohw\GGvaX7lJGIh[XO|YYmsJGlEPTB;MD6wNFQ2KM7:TR?= M{XyWFIxQTd|NEi4
HeLa cells M4e0RXBzd2yrZnXyZZRqd25iYYPzZZk> MXfBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKEinTHGgZ4VtdHNiYomgd5Vt\m:{aH;kZY1qdmViQjDhd5NigSxiSVO1NF0xNjByNEeg{txO MoTWNlA6PzN2OEi=
rat A10 cells NYPBXpRSTnWwY4Tpc44h[XO|YYm= NIfTbXhKdmirYnn0bY9vKG:oIH3pZ5JwfHWkdXzlJIRmeG:ueX3ldol7[XSrb36gbY4hemG2IFGxNEBk\WyuczDhd5Nme3OnZDDhd{Bz\W:{Z3HubZpifGmxbjDv[kBqdnSncoDoZZNmKG2rY4LveJVjfWynIH7leJdwemtiYomgbY5lcXKnY4SgbY1ufW6xZnz1c5Jme2OnbnPlJJRm[2iwaYH1[UwhTUN3ME2wMlAxPyEQvF2= MkLGNlA6PzN2OEi=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Immunofluorescence
tubulin / VE-cadherin; 

PubMed: 29221156     


HUVEC monolayers were treated with 1 μM CA4P for 4 (A, E), 8 (B, F), or 10 (C, G) minutes then fixed and stained for either tubulin (A-D) or VE-cadherin (E-H). HUVEC were also pretreated with 1 μM S1P prior to CA4P treatment; (D,H) show tubulin and VE-cadherin staining following S1P pretreatment followed by 10 minutes CA4P treatment. Tubulin disruption and VE-cadherin rearrangement are both evident from around 8 minutes post CA4P treatment (arrowheads). Tubulin disruption is pronounced by 10 minutes after starting CA4P treatment (*) but tubulin is protected at this timepoint by pretreatment with S1P (**). Scale bars = 5μm.

Actin / N-cadherin / CD31 ; 

PubMed: 29221156     


Untreated co-cultured HUVEC and vSMC stained for CD31 (indicating endothelial cells) and N-cadherin (indicating EC/SMC junctions) display mostly intact CD31 and N-cadherin staining at intercellular junctions (A, C, E), although some cytoplasmic N-cadherin is also evident. Staining for F-actin in (A) and (B), indicated in red, reveals the cytoskeleton of the cells. (A) shows untreated co-cultures in monolayer stained for N-cadherin (green) and actin (red), whilst (B) shows CA4P treated cells. (C) shows a tubular structure, typically formed from around 40% of the co-cultured cells, with the rest forming flat monolayers as in (E); N-cadherin (red) and CD31 (green). CD31 staining was relatively unaffected by CA4P treatment (green staining in (D) and (F) versus (C) and (E)). However, N-cadherin staining appears considerably more intracellular and punctate following CA4P treatment (green staining in (B) versus (A) and red staining in (F) versus (E). The change in cellular distribution of N-cadherin following CA4P treatment was blocked by pre-treatment with 1μM S1P, allowing N-cadherin to retain its intercellular location, although its appearance was less smooth than in untreated cells (red staining in (G)versus (F)). Cells treated with S1P alone also retained intercellular location of N-cadherin, but with a less smooth appearance than in untreated cells (red staining in (H) versus (E)). Yellow in merged images indicates co-localisation at cell-cell junctions. Arrowheads = EC, asterisks = SMC (revealed by lack of CD31 staining). Scalebars = 15μm.

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

Kinase Assay:

[1]

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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]

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  • 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.


    (Only for Reference)
Animal Research:

[5]

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  • 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.
    (Only for Reference)

Solubility (25°C)

In vitro Water 28 mg/mL (63.59 mM)
DMSO Insoluble
Ethanol Insoluble
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

* 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 Information

Molecular Weight 440.29
Formula

C18H19O8P.2Na

CAS No. 168555-66-6
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03014297 Active not recruiting Neuroendocrine Tumors|Everolimus Lowell Anthony MD|University of Kentucky March 6 2017 Phase 1
NCT03014297 Active not recruiting Neuroendocrine Tumors|Everolimus Lowell Anthony MD|University of Kentucky March 6 2017 Phase 1
NCT02641639 Terminated Platinum Resistant Ovarian Cancer Mateon Therapeutics June 2016 Phase 2|Phase 3
NCT02641639 Terminated Platinum Resistant Ovarian Cancer Mateon Therapeutics June 2016 Phase 2|Phase 3
NCT01701349 Withdrawn Anaplastic Thyroid Cancer Mateon Therapeutics March 2015 Phase 3
NCT01701349 Withdrawn Anaplastic Thyroid Cancer Mateon Therapeutics March 2015 Phase 3

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Microtubule Associated Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID