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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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Imatinib Mesylate is orally bioavailability mesylate salt of Imatinib, which is a multi-target inhibitor of v-Abl, c-Kit and PDGFR with IC50 of 0.6 μM, 0.1 μM and 0.1 μM, respectively. |
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Targets
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v-Abl |
PDGFR |
c-Kit |
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IC50 |
600 nM |
100 nM [1] |
100 nM [2] |
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In Vitro
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In vitro assays for inhibition of a panel of tyrosine and serine/threonine protein kinases show that Imatinib inhibits the v-Abl tyrosine kinase and PDGFR potently with an IC50 of 0.6 and 0.1 μM, respectively. [1] Imatinib inhibits the SLF-dependent activation of wild-type c-kit kinase activity with a IC50 for these effects of approximately 0.1 μM, which is similar to the concentration required for inhibition of PDGFR. [2] Imatinib exhibits growth-inhibitory activity on the human bronchial carcinoid cell line NCI-H727 and the human pancreatic carcinoid cell line BON-1 with an IC50 of 32.4 and 32.8 μM, respectively. [3] A recent study shows that Imatinib has the potential to exert its antileukemia effects in chronic myelogenous leukemia by down-regulating hERG1 K(+) channels, which are highly expressed in leukemia cells and appear of exceptional importance in favoring leukemogenesis. [4] |
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In Vivo
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Imatinib produces a different antitumor effect on three xenografted tumors derived from surgical samples of fresh human small cell lung cancers, with 80%, 40% and 78% growth inhibition of SCLC6, SCLC61 and SCLC108 tumors, respectively, and no significant inhibition of SCLC74 growth. [5] In high fat fed ApoE(-/-) mice, Imatinib significantly reduces the high fat-induced lipid staining area by 30%, 27% and 35% compared to high-fat diet untreated controls when dosed by gavage at 10, 20 and 40 mg/kg, respectively, and suppresses carotid artery lipid accumulation. [6] |
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Clinical Trials
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Imatinib is currently being investigated in Phase III clinical trials in patients with Sarcoma. |
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Features
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Protocol
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Kinase Assay
[1]
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| PDGF receptor kinase activity |
PDGF receptor is immunoprecipitated from BALB/c 3T3 cell extracts with rabbit antiserum to the murine PDGF receptor for 2 hours on ice. Protein A-Sepharose beads are used to collect the antigen-antibody complexes. The immunoprecipitates are washed twice with TNET (50 mM Tris, pH 7.5, 140 mM NaCl, 5 mM EDTA, 1% Triton X-100), once with TNE (50 mM Tris, pH 7.5, 140 mM EDTA), and once with kinase buffer (20 mM Tris, pH 7.5,10 mM MgCl2). After stimulation with PDGF (50 ng/mL) for 10 minutes at 4 °C, different concentrations of drug are added to the reaction mixture. PDGF receptor kinase activity is determined by incubation with 10 μCi [7-33P]-ATP and l μM ATP for 10 minutes at 4 °C. Immune complexes are separated by SDS-PAGE on 7.5% gels. |
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Cell Assay
[3]
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| Cell Lines |
BON-1 cells and NCI-H727 cells |
| Concentrations |
~100 μM |
| Incubation Time |
48 hours |
| Methods |
BON-1 cells and NCI-H727 cells are seeded into flat-bottomed 96-well plates in triplicate and allowed to adhere overnight in 10% fetal bovine serum-supplemented DMEM or RPMI 1640 complete medium, respectively; the medium is then exchanged for serum-free medium (negative control) or serum-free medium containing serial dilutions of Imatinib. After 48 hours (control cultures do not reach confluence), the number of metabolically active cells is determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and absorbance is measured in a Packard Spectra microplate reader at 540 nm. Growth inhibition is calculated using the following formula: inhibition rate = (1 ? a / b) × 100%, where a and b are the absorbance values of the treated and control groups, respectively. |
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Animal Study
[5]
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| Animal Models |
SCLC6, SCLC61, SCLC 74 and SCLC108 small cell lung cancers are injected into Swiss mice (nu/nu, female). |
| Formulation |
Imatinib is diluted in water. |
| Doses |
70 or 100 mg/kg |
| Administration |
Administered via i.p. |
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References |
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[1] Buchdunger E, et al. Proc Natl Acad Sci USA, 1995, 92(7), 2558–2562.
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[2] Heinrich MC, et al. Blood. 2000, 96(3), 925-932.
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[3] Yao JC, et al. Clin Cancer Res. 2007, 13(1), 234-240.
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[4] Zheng F, et al. Med Oncol, 2012, 29(3), 2127-2135.
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[5] Decaudin D, et al. Int J Cancer. 2005, 113(5), 849-856.
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[6] Ballinger ML, et al. J Cell Mol Med. 2010,14(6B), 1408-1418.
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