Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland.
Mol Cancer Ther. 2011 Jun;10(6):1007-17. doi: 10.1158/1535-7163.MCT-10-0666. Epub 2011 Apr 12.
Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib.
索拉非尼靶向 Raf/丝裂原活化蛋白激酶、VEGF 和血小板衍生生长因子途径，延长晚期肝细胞癌 (HCC) 患者的生存时间。依维莫司抑制哺乳动物雷帕霉素靶蛋白，该蛋白在 HCC 中过度活跃。为了研究这些药物的抗肿瘤作用是否具有相加作用，我们比较了依维莫司和索拉非尼联合和序贯治疗方案与单药治疗的效果。在 MH 细胞肝内植入后，大鼠随机分为依维莫司 (5mg/kg，2 次/周)、索拉非尼 (7.5mg/kg/d)、联合依维莫司和索拉非尼、序贯索拉非尼 (2 周) 然后依维莫司 (3 周) 或对照组。MRI 定量肿瘤体积。通过免疫印迹定量测定 Erk1/2、4E-BP1 及其磷酸化形式。体外通过主动脉环和管形成测定评估血管生成，体内通过 Vegf-a mRNA 和血管铸型评估血管生成。35 天后，与对照组相比，依维莫司、联合组和序贯组的肿瘤体积分别减少了 60%、85%和 55%(P < 0.01)。联合组的生存时间最长 (P < 0.001)。依维莫司和索拉非尼分别降低了 4E-BP1 和 Erk1/2 的磷酸化。所有治疗后血管生成均减少(P < 0.05)，尽管索拉非尼增加了肝肿瘤中的 Vegf-a mRNA。对照肿瘤中血管芽生丰富，索拉非尼后减少，联合后消失。联合治疗后，腔内血管生成透壁支柱未能融合。依维莫司和索拉非尼联合治疗对 MH 肿瘤的抗肿瘤作用强于单药治疗。依维莫司在索拉非尼序贯治疗后仍具有抗肿瘤作用。这支持依维莫司在 HCC 中的临床应用，无论是与索拉非尼联合应用还是索拉非尼之后应用。
