Imatinib and Dasatinib Inhibit Hemangiosarcoma and Implicate PDGFR-β and Src in Tumor Growth

摘要: Hemangiosarcoma, a natural model of human angiosarcoma, is an aggressive vascular tumor diagnosed commonly in dogs. The documented expression several receptor tyrosine kinases (RTKs) by these tumors makes them attractive targets for therapeutic intervention using kinase inhibitors (TKIs). However, we possess limited knowledge the effects TKIs on hemangiosarcoma as well other soft tissue sarcomas. We report here use imatinib and dasatinib canine their platelet-derived growth factor β (PDGFR-β) Src inhibition. Both reduced cell viability, but was markedly more potent this regard, mediating cytotoxic orders magnitude greater than imatinib. Dasatinib also inhibited phosphorylation shared PDGFR-β target at concentration approximately 1000 times less that needed effectively blocked phosphorylation. augmented response to doxorubicin, suggesting clinical responses likely will be improved both drugs combination; however, significantly (P < .05) effective context. Despite higher concentrations cell-based assays, xenograft model, highlighting disruption PDGFR-β/PDGF signaling may important targeting angiogenic nature tumors. Treatment dog with spontaneously occurring established clinically achievable doses realized dogs provides means investigate effect sarcomas large animal model.