Transarterial chemoembolization with sorafenib in VX2 tumor model of rabbit liver: pharmacokinetics and antitumor effect

Abstract

Purpose To investigate the feasibility, safety and anti-tumor effect of transarterial chemoembolization (TACE) using sorafenib in VX-2 tumor model of rabbit liver. Materials and methods Twenty New Zealand white rabbits with VX2 tumor in the liver were divided into two groups, treated with hepatic arterial administration of 0.5mL of iodized oil alone (TAE-L group) and 0.5mL of iodized oil and 10mg of sorafenib (TAE-S group), respectively. Liquid chromatography tandem mass spectrometry was used to measure the concentration of sorafenib in the peripheral blood and the tumor at 0.5, 1, 2, 4, 24, and 72 hours after treatment. Hepatic enzymes, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1α (HIF-1α) were measured at 0, 24, and 72 hours after treatment. Histopathologic examination was performed to evaluate the degree of tumor necrosis and normal parenchymal damage. Results Access of left hepatic artery was possible in all the rabbits and Lipiodol or emulsion of sorafenib and Lipiodol were delivered successfully as planned. Serum sorafenib concentration peaked at 2 hours after treatment and average tissue concentration was 406.8 times higher than serum concentration. Aspartate aminotransferase and alanine aminotransferase level showed transient elevation in TAE-S group at 24 hours after treatment. Mean serum VEGF and HIF-1α concentrations showed no significant difference between two groups. Degree of ballooning degeneration and coagulation necrosis of peritumoral hepatic parenchyma were more severe in TAE-S group. Mean fraction of tumor necrosis after treatment was significantly higher (p=0.011) in TAE-S group (83.9%) than that in TAE-L group (56.6%). Conclusion TACE using sorafenib was feasible in VX2 tumor model of rabbits, resulting in high intratumoral concentration of sorafenib. Degree of tumor necrosis was significantly higher in TAE-S group than TAE-L group, but more severe toxicity of normal liver tissue occurred.