Multikinase inhibitor sorafenib induces skin toxicities in tumor-bearing mice

To investigate the pathologic changes and pathogenesis of multikinase inhibitor (MKI)-induced skin lesions in an animal model. Tumor-bearing nude mice and BDF1 mice were treated with different doses (30-240 mg/kg, Bid) of sorafenib. The pathology and severity of the skin lesions was assessed and evaluated. The concentration of sorafenib in the skin was also determined. Sorafenib transiently induced skin rash at high doses (120-240 mg/kg). The induced skin lesions had pathological manifestations resembling the observations in human patients. The skin of mice treated with sorafenib had significantly increased pathological scores and thickness of the stratum spinosum compared with the control, and induced more severe cutaneous lesions in nude mice than in BDF1 mice. The severity of skin lesions was correlated with the local concentration of sorafenib in the skin, which was significantly higher in nude mice than in BDF1 mice. Sorafenib treatment significantly increased the expression of F4-80, Ly6G, tumor growth factor (TGF)-1 beta, Smad2/3, alpha-smooth-muscle actin, and proliferating cell nuclear antigen. The severity of skin lesions was positively correlated with the concentration of sorafenib in the skin. Our results suggested the involvement of the TGF-beta 1/Smads signaling pathway in the skin reaction induced by MKIs.