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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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Axitinib (AG-013736) is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM, respectively. |
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Targets
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VEGFR1 |
VEGFR2 |
VEGFR3 |
PDGFRβ |
c-Kit |
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IC50 |
0.1 nM |
0.2 nM |
0.1-0.3 nM |
1.6 nM |
1.7 nM [1] |
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In Vitro
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Axitinib could block the cellular autophosphorylation of VEGFR and VEGF-mediated endothelial cell viability, tube formation, and downstream signaling. Axitinib inhibits the proliferation of variable cell lines with IC50 of >10,000 nM (IGR-N91), 849 nM (IGR-NB8), 274 nM (SH-SY5Y) and 573 nM (non-VEGF stimulated HUVEC). [2] |
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In Vivo
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Axitinib exhibits primary inhibition to orthotopically transplanted models such as M24met (melanoma), HCT-116 (colorectal cancer), and SN12C (renal cell carcinoma). [1] Axitinib delays the tumor growth with 11.4 days compared to the controls (p.o. 30 mg/kg) and decreases the Mean Vessels Density (MVD) to 21, compared to 49 in controls, in IGR-N91 ?ank xenografts. [2] Axitinib significantly inhibits growth and disrupts tumor microvasculature in BT474 breast cancer model at 10-100 mg/kg. [3] Axitinib has shown single-agent activity in variable tumors, including renal cell carcinoma, thyroid cancer, non-small cell lung cancer, and melanoma. |
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Clinical Trials
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Axitinib is currently in Phase III clinical trial in advanced hepatocellular carcinoma. |
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Features
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Axitinib is superior as second-line therapy compared with sorafenib, the current standard of care. |
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Combination Therapy
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Description
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Axitinib orally administrated twice daily at dose of 10 or 30 mg/kg in combination with a maximally tolerated dose of Docetaxel (40 mg/kg once a week) enhance tumor growth delay in the LLC model. Axitinib orally administrated twice daily at dose of 30 mg/kg in combination with Docetaxel at dose of 5 mg/kg produce a robust tumor growth delay in the MDA-MB-435/HAL-luc model. Axitinib orally administrated twice daily at dose of 30 mg/kg in combination with Gemcitabine at dose of 140 mg/kg (i.p., days 1, 4, 7, and 10) significantly enhance the effect of tumor growth delay in the Gemcitabine-resistant BxPC-3 human pancreatic cancer model. [1] |
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Protocol
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Kinase Assay
[1]
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| Cellular receptor kinase phosphorylation assay |
Porcine aorta endothelial (PAE) cells, which overexpress full-length VEGFR2, PDGFRβ, Kit, and NIH-3T3, which overexpress murine VEGFR2 (Flk-1) or PDGFRα, are generated. The 96-well plates are coated with 100 μL/well of 2.5 μg/mL anti-VEGFR2 antibody, 0.75 μg/mL anti-PDGFRβ antibody, 0.25 μg/mL anti-PDGFRα antibody, 0.5 μg/mL anti-KIT antibody, or 1.20 μg/mL anti-Flk-1 antibody to prepare ELISA capture plates. Then phosphorylation of RTK is measured by ELISA. |
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Cell Assay
[2]
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| Cell Lines |
HUVEC, SH-SY5Y, IGR-N91 and IGR-NB8 cells |
| Concentrations |
1 nM - 10 μM |
| Incubation Time |
72 hours |
| Methods |
Cells are seeded in a 96-well plate at a density of 5 × 104 and cultured for 24 hours. Axitinib is added to the cells at concentrations ranging from 1 nM to 10 μM. Cell viability is measured after 72 hours by MTS tetrazolium substrate and IC50 values are calculated. |
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Animal Study
[3]
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| Animal Models |
BT474 breast cancer cells are implanted subcutaneously into Immune-deficient female mice (Nu/nu; age 8–12 weeks). |
| Formulation |
0.5% carboxymethylcellulose (CMC) |
| Doses |
10, 30 or 100 mg/kg |
| Administration |
Oral daily |
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References |
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[1] Hu-Lowe DD, et al. Clin Cancer Res, 2008, 14(22), 7272-7283.
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[2] Rossler, J. et al., Int J Cancer, 2011, 128(11), 2748-2758.
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[3] Wilmes LJ, et al. Magn Reson Imaging, 2007, 25 (3), 319-327.
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