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详细内容
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RTKs transmit a wide array of extracellular signals for regulating differentiation and proliferation to cells. Ligand binding triggers many events such as autophosphorylation of tyrosine residues and receptor dimerization [5].
TT cell line was a human MTC cell line that had an activating C634W RET mutant and was expressing calcitonin. In this cell line, cabozantinib inhibited the autophosphorylation of RET with an IC50 value of 85 nmol/L. In TT cells grown for 72 h in 10% serum, cabozantinib dose-dependently inhibited cell proliferation with an IC50 value of 94 nmol/L [4].
Administrated with cabozantinib daily orally at doses of 10, 30, or 60 mg/kg, nu/nu mice bearing TT xenograft tumors, showed a significantly inhibited tumor growth compared with vehicle-treated group. At both doses of 30 and 60 mg/kg, cabozantinib caused markedly and significantly reduced circulating calcitonin (75%; p< 0.005) in serum compared with vehicle-treated control animals [4].
References:
[1]. Michael G. Doran, Daniel E. Spratt, John Wongvipat, et al. Cabozantinib Resolves Bone Scans in Tumor-Na?ve Mice Harboring Skeletal Injuries. Molecular Imaging, 2014, 13:1-5.
[2]. Rossella Elisei, Martin J. Schlumberger, Stefan P. Müller, et al. Cabozantinib in Progressive Medullary Thyroid Cancer. J. Clin. Oncol., 2013, 31(29):3639-46.
[3]. Razelle Kurzrock, Steven I. Sherman, Douglas W. Ball, et al. Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients with Medullary Thyroid Cancer. J. Clin. Oncol., 2011, 29(19):2660-6.
[4]. Frauke Bentzien, Marcus Zuzow, Nathan Heald, et al. In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer. Thyroid, 2013, 23(12):1569-1577.
[5]. Xianhua Piao, Robert Paulson, Peter van?der?Geer, et al. Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1. Proc. Natl. Acad. Sci. USA., 1996, 93(25):14665-14669.
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