Lenvatinib (E7080) is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. Lenvatinib was found to be transformed to a GSH conjugate, through displacement of an O-aryl moiety, at the quinoline part of the molecule in the liver and kidneys. The GSH conjugate underwent further hydrolysis by γ-glutamyltranspeptidase and dipeptidases, followed by intramolecular rearrangement, to form N-cysteinyl quinoline derivatives, which were dimerized to form disulfide dimers and also formed an N,S-cysteinyl diquinoline derivative. In urine, a thioacetic acid conjugate of the quinoline was also observed as one of the major metabolites of lenvatinib. Lenvatinib is a 4-O-aryl quinoline derivative, and such compounds have been known to undergo conjugation with GSH, accompanied by release of the O-aryl moiety. Because of intramolecular rearrangement in the case of lenvatinib, hydrolysis of the GSH conjugate yielded N-cysteinylglycine and N-cysteine conjugates instead of the corresponding S-conjugates. Because the N-substituted derivatives possess free sulfhydryl groups, dimerization through disulfide bonds and another nucleophilic substitution reaction with lenvatinib resulted in the formation of disulfanyl dimers and an N,S-cysteinyl diquinoline derivative, respectively. Oral administration of Lenvatinib inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and Lenvatinib causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling.
|Cell lines||H146 cells|
|Preparation method||Proliferation assay
H146 (1.2 3 103 cells/50 lL/well) in SFM containing 0.5% BSA were cultured in 96-well multi-plates. After overnight culture at 37℃, SFM (150 lL/well) containing 0.5% FBS and several concentrations of SCF were added with or without several concentrations of compound. After culture for 72 hr, the ratios of surviving cells were measured by WST-1.
|Incubation time||72 hr|
|Animal models||Female BALB/c nude mice H146 cells tumor xenograft model|
|Dosages||30, 100mg/kg twice a day from day 1 to day 21|
|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.
A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours.
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Development and validation of LC-MS/MS assays for the quantification of E7080 and metabolites in various human biological matrices.
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E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion.
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E7080 suppresses hematogenous multiple organ metastases of lung cancer cells with nonmutated epidermal growth factor receptor.
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E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition.
Matsui J, et al. Int J Cancer. 2008 Feb 1;122(3):664-71. PMID: 17943726.
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