Multikinase inhibitor sorafenib transiently promotes necrosis after radiofrequency ablation in rat liver but activates growth signals
Multikinase inhibitor sorafenib transiently promotes necrosis after radiofrequency ablation in rat liver but activates growth signals
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DOI：
10.1016/j.ejrad.2011.04.042
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发表时间：
2012-07-01
影响因子：
3.3
通讯作者：
Geier, Andreas
中科院分区：
文献类型：
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作者：
Mertens, Joachim C.;Martin, Ina V.;Geier, Andreas
目的：为探讨索拉非尼联合射频消融治疗对大鼠肝组织的影响，对大鼠肝组织坏死体积、组织修复和肝细胞生长信号进行了分析。射频消融（RFA）是目前广泛应用于肝细胞癌（HCC）的治疗方法。在正在进行的临床试验中，放射性消融术与多酪氨酸激酶抑制剂索拉非尼联合使用。这种联合治疗是否影响肝组织修复尚不清楚。材料和方法：雄性Sprague道利（SD）大鼠接受RFA或假穿刺，同时接受索拉非尼（从第2天起5 mg/kg，每日一次）或溶剂。从切除的标本计算坏死体积。Ki 67和CD 31免疫荧光法分别测定细胞增殖和微血管密度。肝细胞生长因子（HGF）、表皮生长因子（EGF）和血管内皮生长因子（VEGF）的mRNA表达被定量。结果：虽然在第1天所有治疗组的消融尺寸相同，但索拉非尼治疗的动物显示持续的坏死（219 +/- 24 vs. 88 +/- 52 mm（3）对照组; P = 0.03），丙氨酸氨基转移酶（ALT）和谷氨酸脱氢酶（GLDH）升高（76 +/- 37 vs. 47 +/- 58 mm（3）; P = 0.50）。到第7天，治疗组的坏死体积相等。Ki 67和CD 31染色显示索拉非尼给药后第1天和第3天增殖和微血管密度降低。结论：索拉非尼治疗后肝组织中生长因子HGF和EGF的表达明显增加，索拉非尼治疗后肝组织中生长因子HGF和EGF的表达明显增加，索拉非尼治疗后肝组织中生长因子HGF和EGF的表达明显增加。组织修复的延迟在第7天被克服，推测是通过生长信号的短暂代偿性过表达。基于动物研究的这些数据，有必要进一步研究佐剂索拉非尼在人体中的作用。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Aim: To investigate the effects of sorafenib when combined with radiofrequency ablation treatment in liver tissue, the necrosis volume, tissue repair and hepatocellular growth signals were analyzed in rats. Radiofrequency ablation (RFA) is a widely applied treatment for hepatocellular carcinoma (HCC). Radiofrequency ablation is combined with the multi-tyrosinkinase-inhibitor sorafenib in ongoing clinical trials. Whether this combination treatment affects liver tissue repair is unknown.Materials and methods: Male Sprague Dawley (SD) rats received RFA or sham puncture with concomitant sorafenib (5 mg/kg qd from day 2) or vehicle. Necrosis volume was calculated from resected specimens. Proliferation and micro vessel density were determined by Ki67 and CD31 immunofluorescence, respectively. mRNA expression of hepatocyte growth factor (HGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) was quantified.Results: While ablation size was identical in all treatment groups at day 1, sorafenib treated animals showed sustained necroses (219 +/- 24 vs. 88 +/- 52 mm(3) in controls; P = 0.03), elevated alanine aminotransferase (ALT) and elevated glutamate dehydrogenase (GLDH) (76 +/- 37 vs. 47 +/- 58 mm(3); P = 0.50) at day 3. By day 7 necrosis volumes equalized for the treatment groups. Ki67 and CD31 staining showed reduced proliferation and micro vessel density at days 1 and 3 following sorafenib. Growth factors HGF and EGF were significantly overexpressed in liver tissue after sorafenib.Conclusion: Sorafenib initially promotes necrosis after RFA in liver tissue. The delay in tissue repair is overcome at day 7 presumably by transient compensatory overexpression of growth signals. Based on these data from animal studies further investigation of adjuvant sorafenib in humans is warranted. (C) 2011 Elsevier Ireland Ltd. All rights reserved.