Axitinib

Biological Activity

Axitinib blocked phosphorylation of VEGFR-2 and VEGFR-3 with average IC50s of 0.2 and 0.1 to 0.3 nM.Axitinib (also known as AG013736) is a small molecule tyrosine kinase inhibitor.It inhibits multiple targets, including VEGFR-1, VEGFR-2, VEGFR-3, platelet derived growth factor receptor (PDGFR), and cKIT (CD117). It has been shown to significantly inhibit growth of breast cancer in xenograft models and has been successful in trials with renal cell carcinoma (RCC) and several other tumor types.

Protocol

Cell Experiment
Cell lines	HUVEC, SH-SY5Y, IGR-N91 and IGR-NB8 cell lines
Preparation method	MTS cell proliferation assay HUVEC, SH-SY5Y, IGR-N91 and IGR-NB8 cell lines were seeded at 5,000 cells per well in a 96-well plate and left to settle overnight in EMBV R-2 or DMEM with 10% fetal calf serum. The cells were treated with axitinib at concentrations ranging from 1 nmol/l to 10 lmol/l. Cell viability was determined after 72 hr using MTS tetrazolium substrate (CellTiter 96 Aqueous One Solution Cell Proliferation Assay; Promega Corporation, Charbonnieres, France) and colorimetric measurement at 490 nm in an automatic plate reader (Elx808; Fisher Bioblock Scientific SAS, Illkirch, France). IC50 values were calculated using GraphPadV R Prism software (version 3.00).
Concentrations	1 nmol/l to 10 lmol/l
Incubation time	72 hr

Animal Experiment
Animal models	IGR-N91 xenografts with female SPF-Swiss athymic nude mice at 6–8 weeks of age
Formulation	0.5% CMC
Dosages	30 mg/kg BID for 2 weeks
Administration	oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

Customer Product Validations & Biological Datas

	Source	Int J Cancer (2017) . Figure 6. Axitinib (20 mg/kg, Abmole Bioscience)
	Method
	Cell Lines	Hmga2/T mice
	Concentrations	20mg/kg
	Incubation Time	6 weeks
	Results	Together, these results show that, while bromocriptine and/or axitinib were able to correct structuralabnormalities of tumoral vessels with a similar efficacy, only the combination treatment restored their function.
	Rating

	Source	Int J Cancer (2017) . Figure 5. Axitinib (20 mg/kg, Abmole Bioscience)
	Method
	Cell Lines	Hmga2/T mice
	Concentrations	20mg/kg
	Incubation Time	6 weeks
	Results	Analysis of pituitary vasculature in various conditions and morphometric measurements of blood vessels demonstrate that D2R agonist or axitinib had an equivalent capacity to improve structural defects present in tumoral blood vessels and that the combination treatment did not lead to a significant advantage.
	Rating

	Source	Int J Cancer (2017) . Figure 4. Axitinib (20 mg/kg, Abmole Bioscience)
	Method
	Cell Lines	Hmga2/T mice
	Concentrations	20mg/kg
	Incubation Time	6 weeks
	Results	Importantly, the expression of Angpt1 and Prok1, which was upregulated in response to bromocriptine treatment, was unchanged and remained low after axitinib treatment (Fig. 4d).
	Rating

Product Citations

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  Int J Cancer. 2017 May 1;140(9):2150-2161.

  Complementary actions of dopamine D2 receptor agonist and anti-vegf therapy on tumoral vessel normalization in a transgenic mouse model
  Axitinib purchased from AbMole

References

Comprehensive overview of axitinib development in solid malignancies: focus on metastatic renal cell carcinoma.
Carmichael et al. Clin Adv Hematol Oncol. 2012 May;10(5):307-14. PMID: 22706540.

Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers.
Pithavala et al. Cancer Chemother Pharmacol. 2012 Jul;70(1):103-12. PMID: 22644797.