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Research Area
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Description
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Solid tumours, Chronic myeloid leukaemia |
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Biological Activity
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Description
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Cediranib (AZD2171) is a highly potent VEGFR2 inhibitor with IC50 of 0.5 nM. |
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Targets
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VEGFR2 |
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IC50 |
0.5 nM [1] |
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In Vitro
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Cediranib inhibits VEGF-stimulated proliferation with IC50 of 0.4 nM. Cediranib suppresses PDGF-AA with IC50 of 0.04 μM in MG63 cell lines. Cediranib has been shown to block Flt1-associated kinase with IC50 of 5 nM and VEGF-C and VEGF-D receptor Flt-4 with IC50 less than 3 nM. In addition, the IC50 values for inhibition of c-Kit and PDGFRβ tyrosine kinase are 2 nM and 5 nM respectively. Furthermore, no inhibition of enzyme activity is observed when 10 μM Cediranib is assayed with 100 μM ATP against AMPK, Chk1 Akt/PKB and others. Micromolar concentrations of Cediranib are needed to prevent tumor cell proliferation in vitro. [1] |
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In Vivo
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Cediranib even suppresses tubule sprouting at subnanomolar concentrations and inhibits VEGF-induced angiogenesis. Cediranib causes hypertrophy in bone growth plate and prevents luteal development in ovary. These are physiological processes that are dependent upon angiogenesis. Cediranib shows broad spectrum activity in human tumor models at doses that are well tolerated. [1] Besides, Cediranib causes regression of vascular tissues in human lung tumor xenografts. [2] |
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Clinical Trials
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Cediranib is currently being evaluated in a phase II clinical trial for the treatment of advanced solid tumors. |
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Features
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Protocol
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Kinase Assay
[1]
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| Kinase inhibition |
Cediranib is dissolved in DMSO at a concentration of 10 mM. All enzyme assays are run at, or just below, the respective Km for ATP (0.2 - 30 μM). The inhibitory activity of Cediranib is determined against a range of recombinant tyrosine kinases [KDR, Flt-1, Flt-4, c-Kit, PDGFRα, PDGFRβ, CSF-1R, Flt-3, FGFR1, Src, Abl, epidermal growth factor receptor (EGFR), ErbB2, Aurora A, and Aurora B] using ELISA. Selectivity versus CDK2 and CDK4 serine/threonine kinases is examined using scintillation proximity assays with a retinoblastoma substrate and [γ-sup>33P]ATP. Activity of Cediranib is compared to MAPK kinase (MEK), which shows dual specificity. It is determined using a MAPK substrate, [γ-33P]ATP, and paper capture/scintillation counting. |
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Cell Assay
[1]
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| Cell Lines |
HUVEC cell line |
| Concentrations |
10 μM |
| Incubation Time |
72 hours |
| Methods |
The proliferation of the HUVEC cell line is evaluated in the presence and absence of growth factors by measuring 3H-thymidine incorporation following a 4-day incubation period. Proliferation of MG63 osteosarcoma cells is induced by PDGF-AA, which selectively activates signaling of the PDGFRα homodimer. HUVEC and MG63 osteosarcoma cells are cultured in DMEM without phenol red containing 1% charcoal stripped FCS, 2 mM glutamine, and 1% nonessential amino acids for 24 hours. Cediranib or vehicle is added with PDGF-AA ligand (50 ng/mL) and plates incubated for another 72 hours. Cellular proliferation is determined using bromodeoxyuridine ELISA. |
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Animal Study
[1]
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| Animal Models |
PC-3, Calu-6, SKOV-3, MDA-MB-231, and SW620 tumors in female nude (nu/nu genotype) mice |
| Formulation |
Suspended in 1% (w/v) aqueous polysorbate 80 |
| Doses |
0.75-6 mg/kg/day |
| Administration |
Orally |
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