A multi-targeted receptor tyrosine kinase inhibitor
Toceranib is an inhibitor which blocks various tyrosine kinases expressed on the cell surface. Receptor tyrosine kinases (RTKs) are excellent candidates for molecular targeted therapy, because they play key roles in controlling cell proliferation and survival and are frequently dysregulated in a variety of malignancies.
In vitro: Toceranib inhibited KIT phosphorylation and cell proliferation in a dose-dependent manner in the treatment-na?ve, parental C2 line (IC50 < 10 nM). In addition, chronic TOC exposure resulted in c-kit mRNA and KIT protein overexpression in the TOC-resistant sublines [1].
In vivo: Fourteen dogs with advanced mast cell tumors (MCTs) were enrolled in a prevoius study, among which 11 dogs were evaluable for KIT target modulation. Of these, eight MCTs showed reduced levels of phosphorylated KIT relative to total KIT after treatment with Toceranib, compared with pretreatment biopsies. All four evaluable MCTs expressing ITD mutant c-kit showed modulation of KIT phosphorylation, as did four of seven tumors expressing non-ITD c-kit. [2].
Clinical trials: Currenlty no clinical data are available.
参考文献:
[1] Halsey CH, Gustafson DL, Rose BJ, Wolf-Ringwall A, Burnett RC, Duval DL, Avery AC, Thamm DH.? Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia?) in canine mast cell tumor. BMC Vet Res. 2014;10:105. doi: 10.1186/1746-6148-10-105.
[2] Pryer NK, Lee LB, Zadovaskaya R, Yu X, Sukbuntherng J, Cherrington JM, London CA.?? Proof of target for SU11654: inhibition of KIT phosphorylation in canine mast cell tumors. Clin Cancer Res. 2003;9(15):5729-34.
Cell experiment: | The c-kit mutant canine C2 mastocytoma cell line, derived from a spontaneously occurring cutaneous mast cell tumors (MCTs), is used as the parental cell line. Cells are propagated in RPMI 1640 supplemented with 2 mM L-glutamine, 10% FBS, 100 g/mL Streptomycin, and 100 U/mL Penicillin in a 37°C incubator under a humidified atmosphere of 5% CO2. Toceranib-resistant C2 cells are selected by growing C2 cells in concentrations of Toceranib ranging from 0.02 uM to 0.3 uM and increasing in 0.025-0.05 uM increments. Three independent, Toceranib -resistant sublines are established over a period of 7 months[2]. |
Animal experiment: | Dogs[3]Fifteen client-owned dogs with advanced tumors are used. Dogs receive Toceranib at 2.75 mg/kg once every other day. After 2 weeks, oral cyclophosphamide (CYC) is added at 15 mg/m2 daily. Numbers of Treg and lymphocyte subsets are measured in blood by flow cytometry during the 8-week study period. Serum concentrations of IFN-γ are measured by ELISA. |
参考文献: [1]. London CA, et al. Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies. Clin Cancer Res. 2003 Jul;9(7):2755-68. | |
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