Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume University, Fukuoka, Japan.
Clin Cancer Res. 2012 Jul 15;18(14):3924-33. doi: 10.1158/1078-0432.CCR-11-2041. Epub 2012 May 18.
VEGF, EGF, and TGF-α are expressed in hepatocellular carcinomas (HCC) and play a role in its growth. Vandetanib, a multikinase inhibitor, suppresses the phosphorylation of VEGF receptor 2 (VEGFR-2) and EGF receptor (EGFR). The aim of this study was to clarify the antitumor effect of vandetanib in mouse HCCs.
We evaluated the effects of vandetanib on proliferation of human umbilical vein endothelial cells (HUVEC) and three hepatoma cell lines, as well as the phosphorylation of VEGFR-2 and EGFR in these cells. Mice were implanted with hepatoma cells subcutaneously or orthotopically in the liver and treated with 50 or 75 mg/kg vandetanib. We analyzed the effects of treatment on tumor cell proliferation and apoptosis, vessel density, phosphorylation of VEGFR-2 and EGFR, and production of VEGF, TGF-α, and EGF in tumor tissues. Adverse events on vandetanib administration were also investigated.
Vandetanib suppressed phosphorylation of VEGFR-2 in HUVECs and EGFR in hepatoma cells and inhibited cell proliferation. In tumor-bearing mice, vandetanib suppressed phosphorylation of VEGFR-2 and EGFR in tumor tissues, significantly reduced tumor vessel density, enhanced tumor cell apoptosis, suppressed tumor growth, improved survival, reduced number of intrahepatic metastases, and upregulated VEGF, TGF-α, and EGF in tumor tissues. Treatment with vandetanib was not associated with serious adverse events, including alanine aminotransferase abnormality, bone marrow suppression, or body weight loss.
The antitumor effects of vandetanib in mice suggest that it is a potentially suitable and safe chemotherapeutic agent for HCCs.
血管内皮生长因子（VEGF）、表皮生长因子（EGF）和转化生长因子-α（TGF-α）在肝细胞癌（HCC）中表达，并在其生长中发挥作用。凡德他尼是一种多激酶抑制剂，可抑制血管内皮生长因子受体 2（VEGFR-2）和表皮生长因子受体（EGFR）的磷酸化。本研究旨在阐明凡德他尼对小鼠 HCC 的抗肿瘤作用。
我们评估了凡德他尼对人脐静脉内皮细胞（HUVEC）和三种肝癌细胞系增殖的影响，以及这些细胞中 VEGFR-2 和 EGFR 的磷酸化。将肝癌细胞皮下或原位植入小鼠肝脏，并给予 50 或 75mg/kg 凡德他尼治疗。我们分析了治疗对肿瘤细胞增殖和凋亡、血管密度、VEGFR-2 和 EGFR 磷酸化以及肿瘤组织中 VEGF、TGF-α和 EGF 产生的影响。还研究了凡德他尼给药的不良反应。
凡德他尼抑制了 HUVEC 中 VEGFR-2 的磷酸化和肝癌细胞中 EGFR 的磷酸化，并抑制了细胞增殖。在荷瘤小鼠中，凡德他尼抑制了肿瘤组织中 VEGFR-2 和 EGFR 的磷酸化，显著降低了肿瘤血管密度，增强了肿瘤细胞凋亡，抑制了肿瘤生长，提高了生存率，减少了肝内转移的数量，并上调了肿瘤组织中的 VEGF、TGF-α和 EGF。凡德他尼治疗与严重不良事件无关，包括丙氨酸氨基转移酶异常、骨髓抑制或体重减轻。
凡德他尼在小鼠中的抗肿瘤作用表明，它是一种潜在合适且安全的 HCC 化疗药物。
