Dasatinib (BMS-354825) is a small molecule inhibitor of both the SRC and BCR/ABL tyrosine kinases, with IC50's for the isolated kinases of 0.55 and 3.0 nM, respectively. Dasatinib also inhibits Lyn (IC50 = 8.5 nM) and Src (IC50 = 3.0 nM) kinase activities in vitro using 0.1 mg/mL poly (Glu4-Tyr) as the substrate. Dasatinib has greater potency than imatinib mesylate and has activity against the majority of kinase mutations in imatinib-resistant chronic myeloid leukemia.
|Cell lines||Ba/F3 cell lines|
|Preparation method||Cellular proliferation assays. Ba/F3 cell lines were plated in triplicate and incubated with escalating concentrations of imatinib, AMN107, or BMS-354825 for 72 hours. Proliferation was measured using a methanethiosulfonate-based viability assay (CellTiter96 Aqueous One Solution Reagent; Promega). IC50 and IC90 values are reported as the mean of three independent experiments done in quadruplicate. The inhibitor concentration ranges for IC50 and IC90 determinations were 0 to 2,000 nmol/L (imatinib and AMN107) or 0 to 32 nmol/L (BMS-354825). The imatinib concentration range was extended to 6,400 nmol/L for mutants with IC50 >2,000 nmol/L. The BMS-354825 concentration range was extended to 200 nmol/L for mutant T315I.|
|Incubation time||72 h|
|Animal models||primary human Ph+ B-ALL xenografts|
|Formulation||dissolved in a mixture of polypropylene glycol (Sigma-Aldrich) diluted in water (50:50)|
|Dosages||5 mg/kg/day for two weeks|
|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.
|Source||Biochimica et Biophysica Acta (2017) . Figure 7. Dasatinib was supplied from Abmole Bioscience (Houston, TX, USA).|
|Cell Lines||MDA-MB-231 cells|
|Incubation Time||24 h|
|Results||Apoptosis analysis by flow cytometry showed that shCtrl- and shCav-1-transfected MDA-MB-231 cells treated with Dasatinib for 24 h maintained high cell viability (N80%), with no disparity in apoptosis (Fig. 7B).|
Biochim Biophys Acta. 2017 Jan;1864(1):12-22.
Pulmonary arterial hypertension caused by treatment with dasatinib for chronic myeloid leukemia critical alert.
Sano et al. Intern Med. 2012;51(17):2337-40. PMID: 22975544.
Anti-tumor T cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40.
Yang et al. Blood. 2012 Aug 30. PMID: 22936666.
A randomized trial of dasatinib 100 mg vs imatinib 400 mg in newly diagnosed chronic phase chromic myeloid leukemia.
Radich et al. Blood. 2012 Aug 28. PMID: 22915637.
Dasatinib in chronic myeloid leukemia: A limited Indian experience.
Sharma et al. Asia Pac J Clin Oncol. 2012 Jul 6. PMID: 22897916.
Active efflux of dasatinib from the brain limits efficacy against murine glioblastoma: broad implications for the clinical use of molecularly-targeted agents.
Agarwal et al. Mol Cancer Ther. 2012 Aug 13. PMID: 22891038.
Simple methodology for the therapeutic drug monitoring of the tyrosine kinase inhibitors dasatinib and imatinib.
Birch et al. Biomed Chromatogr. 2012 Aug 6. PMID: 22886846.
Dasatinib inhibits leukaemic cell survival by decreasing PRH/Hhex phosphorylation resulting in increased repression of VEGF signalling genes.
Noy et al. Leuk Res. 2012 Aug 5. PMID: 22874537.
Simultaneous measurement of imatinib, nilotinib and dasatinib in dried blood spot by ultra high performance liquid chromatography tandem mass spectrometry.
Kralj et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Aug 15;903:150-6. PMID: 22857863.
Comparison of the effects of two kinase inhibitors, sorafenib and dasatinib, on chronic lymphocytic leukemia cells.
Kuckertz et al. Onkologie. 2012;35(7-8):420-6. PMID: 22846973.
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Dasatinib(BMS-354825) hydrochloride is a potent and dual Abl/ Src inhibitor IC50 of ＜1 nM/0.8 nM respectively; also inhibit c-Kit (WT)/c-Kit (D816V) with IC50 of 79 nM/37 nM.
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