Background
KRN 633 is a selective inhibitor of VEGFR-1, VEGFR-2 and VEGFR-3 with IC50 value of 170 nM, 160 nM and 125 nM [1].
Vascular endothelial growth factor receptor (VEGFR) is a protein and plays an important role in tumor angiogenesis by cooperating with its ligand VEGF [1].
KRN 633 is a potent VEGFR inhibitor. When tested with HUVECs, KRN 633 inhibited the cell proliferation that mediated by VEGF with the IC50 value of 14.9 nmol/L and suppressed the capillary tube formation by ~50% at the dose of 10 nmol/L [1].
In mid-pregnant mice model, KRN633 was used at the dose of 5 mg/kg once daily from embryonic day 13.5 until the day of delivery and the effect on vascular growth was slightly delayed on postnatal day 4 (P4) and on P8 it was observed that KRN633 resulted in the decreased numbers of central arteries and veins and abnormal branching of the central arteries [2]. When tested with athymic mouse xenograft HT29 cells model, administration of KRN633 inhibited tumor growth as ~90% from the initial tumor volume rangs from 500-667 mm3, while had less effect Du145 xenograft mouse models by inhibiting tumor angiogenesis and vascular permeability [1].
参考文献:
[1].? Nakamura, K., et al., KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth. Mol Cancer Ther, 2004. 3(12): p. 1639-49.
[2].? Morita, A., et al., Treatment of mid-pregnant mice with KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, induces abnormal retinal vascular patterning in their newborn pups. Birth Defects Res B Dev Reprod Toxicol, 2014. 101(4): p. 293-9.
Protocol
Kinase experiment: | Cell-free kinase assays are done to obtain IC50 values against a variety of recombinant receptor and non-RTKs. KRN-633 is tested from 0.3 nM to 10 μM. All assays are done in quadruplicate with 1 μM ATP[1]. |
Cell experiment: | A549, Ls174T, HT29, DU145, LNCap, and PC-3 cells cancer cells are cultured for 24 hours before adding KRN-633 (0.01 to 10 μM) or vehicle (0.1% DMSO in medium) and then grow for a further 96 hours. Cell viability is measured using WST-1 reagent. The percentage viability is determined relative to the untreated control[1]. |
Animal experiment: | Rats: Human tumor xenografts are established in the hind flank of athymic rats (BALB/cA, Jcl-nu). Rats are randomized into groups of five at the point when the tumors reach the average size indicated (162 to 657 mm3) and are then treated with KRN-633 or vehicle, either once (qd) or twice (bid) per day, at the dosages shown. The percentage of tumor growth inhibition compared with the vehicle-treated group is calculated on the day after the last treatment (day 14)[1]. Mice: The mice are randomized into groups of five at the point when the tumors reached the average sizes: 103 to 260 mm3 or 500 to 667 mm3. They are then treated with KRN-633 or vehicle, either once (qd) or twice (bid) per day, at the dosages of 10-100 mg/kg. The percentage of tumor growth inhibition (TGI) compared with the vehicle-treated group is calculated on the day after the last treatment[1]. |
参考文献: [1]. Nakamura K, et al. KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth. Mol Cancer Ther. 2004 Dec;3(12):1639-49. |
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