Vandetanib Dihydrochloride (PTK787) is an orally VEGF receptors inhibitor that inhibits angiogenesis (IC50 = 37 nM and 77 nM for KDR and Flt-1 respectively). The vascular endothelial growth factor (VEGF) is a central mediator of tumor-induced angiogenesis. Vandetanib (PTK787) was hypothesized that dual inhibition of VEGF signaling by inhibition of VEGF production and VEGF receptor signaling leads to synergistic anti-tumor effects. Effects of vatalanib and everolimus on cell proliferation, cell cycle, apoptosis and signal transduction were examined in three gastric cancer cell lines in vitro. Vatalanib abolished endothelial cell tube formation, whereas inhibition of tube formation by everolimus was incomplete. In vivo, the combination of vatalanib with everolimus was superior to single agent treatments and reduced tumor size by about 50% relative to everolimus monotherapy (p < 0.005). Furthermore, Vatalanib dihydrochloride shows significant inhibition of hepatocellular carcinoma cells growth and enhances the IFN/5-FU induced apoptosis by increasing proteins levels of Bax and reduced Bcl-xL and Bcl-2.
|Preparation method||Endothelial Cell Proliferation Assays.
As a test of the ability of PTK787/ZK 222584 to inhibit a functional response to VEGF, an endothelial cell proliferation assay, based on BrdUrd incorporation was used (Biotrak Cell Proliferation System V.2, Amersham, England). Subconfluent HUVECs were seeded at a density of 5 3 103 cells/well into 96-well plates coated with 1.5% gelatin and then incubated at 37°C and 5% CO2 in growth medium. After 24 h, growth medium was replaced by basal medium containing 1.5% FCS and a constant concentration of VEGF (50 ng/ml), bFGF (0.5 ng/ml), or FCS (5%), in the presence or absence of PTK787/ZK 222584. As a control, wells without growth factor were also included. After 24 h of incubation, BrdUrd labeling solution was added, and cells incubated an additional 24 h before fixation, blocking, and addition of peroxidase-labeled anti-BrdUrd antibody. Bound antibody was then detected using 3,395,59-tetramethylbenzidine substrate, which results in a colored reaction product that is quantified spectrophotometrically at 450 nm.
|Incubation time||24 h|
|Animal models||Nude Mouse Human Tumor Xenograft Model|
|Dosages||25 to 100 mg/kg once or twice dail|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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 Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 30 mg/mL|
Effects of vatalanib on tumor growth can be potentiated by mTOR blockade in vivo.
Jaeger-Lansky A, et al. Cancer Biol Ther. 2010 Jun;9(11):919-27. PMID: 20404549.
PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration.
Wood JM, et al. Cancer Res. 2000 Apr 15;60(8):2178-89. PMID: 10786682.
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BAW2881 (NVP-BAW2881) is a potent and selective VEGFR2 inhibitor with activity to inhibit chronic and acute skin inflammation.
SU 1498 is a selective inhibitor of the receptor tyrosine kinase VEGF receptor 2 (VEGFR2, aka FLK1; IC50 = 700 nM).
Avitinib maleate is a pyrrolopyrimidine-based irreversible epidermal growth factor receptor (EGFR) inhibitor with an IC50 of 7.68 nM.
Fruquintinib (HMPL-013) is a highly potent and selective VEGFR 1/2/3 inhibitor with IC50s of 33, 0.35, and 35 nM, respectively.
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