| Vandetanib is an orally bioavailable small molecule tyrosine kinase inhibitor of multiple growth factor receptors, including RET (rearrange during transfection), vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR). In recombinant enzyme assays, IC50 values of vandetanib for VEGFR-2, VEGFR-3, EGFR and RET are 40, 110, 500 and 130 nM, respectively. IC50 values of vandetanib for the liver different human HCC cell lines, Sk-Hep-1, Alexander, HepG2, HLF and Chang, are 3.35, 0.58, 3.16, 1.62 and 5.02 µM, respectively. Furthermore, treatment with vandetanib (IC50) completely inhibits the p-EGFR form after 6 hours, with complete recovery of the receptor baseline expression after 1 day?? exposure in the HCC cell lines. Vandetanib inhibits migration of HCC cells (HLF treated with 1.62 µM vandetanib and Sk-Hep1 treated with 3.35 µM vandetanib) on Laminin-5 and Fibronectin, and invasion through matrigel.[1] The IC50 values of vandetanib in PC-9 and vandetanib-resistant PC-9/VanR cell line determined by MTT assay are 91 nM and 4.6 µM, respectively.[2] Vandetanib has IC50 values of 4.2, 4.2, 1.3 and 1.4 µM for KB-3-1, C-A120, S1 and S1-M1-80 cells, respectively. Besides, clinically attainable but non-toxic doses of vandetanib (1 µM in KB-3-1 and C-A120 or 0.2 µM in S1 and S1-M1-80) significantly enhance the sensitivity of multiple drug resistant (MDR) cancer cells to ABCC1 (ATP-binding cassette C1 subfamily) or ABCG2 (ATP-binding cassette G2 subfamily) substrate antitumor drugs. Vandetanib significantly increases the intracellular accumulation of doxorubicin and rhodamine 123, substrates of ABCC1 and ABCG2 respectively, in a dose-dependent manner.[3] In an in vivo xenograft model, vandetanib effectively inhibits the growth of PC-9 and PC-9/VanR tumors at almost the same rate through the antiangiogenesis effects of VEGFR-2 inhibition.[2] In HCC827 xenografts (wild-type K-RAS, EGFR exon 19 del), vandetanib (50 mg/kg; oral daily) causes complete and sustained regressions of large tumors with a mean volume greater than 1,000 mm3 at the time of treatment initiation. By 4 days of vandetanib treatment mean tumor volume is reduced by half (to 492 mm3) and by 11 days of treatment all tumors are barely palpable (mean tumor volume 66 mm3).[4] |
