Axitinib (AG-013736), an Oral Specific VEGFR TKI, Shows Potential Therapeutic Utility Against Cholangiocarcinoma
Axitinib (AG-013736), an Oral Specific VEGFR TKI, Shows Potential Therapeutic Utility Against Cholangiocarcinoma
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DOI：
10.1093/jjco/hyu045
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发表时间：
2014-06-01
影响因子：
2.4
通讯作者：
Shibata, Tatsuhiro
中科院分区：
文献类型：
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作者：
Takahashi, Hiroyuki;Ojima, Hidenori;Shibata, Tatsuhiro
胆管癌是一种难治性恶性肿瘤，近年来其发病率在世界范围内呈上升趋势。血管新生在包括胆管癌在内的各种实体癌的生长中起重要作用。血管内皮生长因子在肿瘤诱导的血管生成中起重要作用，其表达与胆管癌的进展和预后有关。这项研究检查了阿西替尼是否（AG-013736，INLYTA（A（R），一种有效的和选择性的血管内皮生长因子受体1、2和3的第二代抑制剂，可能是一种潜在的有用的治疗剂胆管癌。我们进行了血管生成的表达谱分析，在8个胆管癌细胞系中检测血管内皮生长因子相关分子的表达，发现其中3个细胞系显示血管内皮生长因子的高表达。其中，我们检测了阿西替尼对NCC-BD 1的体内抗肿瘤作用（吉西他滨敏感的肝外胆管癌细胞系）和TKKK（吉西他滨耐药肝内胆管癌细胞系）皮下异种移植物模型。口服阿昔替尼6 mg kg（-1）day（-1）显著抑制TKKK异种移植物的生长。（P < 0.05），以及30 mg kg（-1）day（-1）的NCC-BD 1异种移植物的生长（P < 0.05）。治疗后的肿瘤显示微血管密度和肿瘤细胞增殖指数显着下降，轻微但显着增加的凋亡指数与未经处理的tumors.Our研究结果表明，阿昔替尼应该是一个有前途的治疗血管内皮生长因子表达的胆管癌，无论肿瘤的起源和吉西他滨的敏感性。
Cholangiocarcinoma is a refractory cancer whose incidence has been increasing worldwide in recent years. Neoangiogenesis plays an important role in the growth of various solid cancers, including cholangiocarcinoma. Vascular endothelial growth factor plays an important role in tumor-induced angiogenesis and its expression is associated with the progression and prognosis of cholangiocarcinoma. This study examined whether axitinib (AG-013736, INLYTA(A (R))), a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, could be a potentially useful therapeutic agent for cholangiocarcinoma.We performed expression profiling of angiogenesis-related molecules in eight cholangiocarcinoma cell lines and found that three of them showed high vascular endothelial growth factor expression. Among them, we examined the in vivo anti-tumor effect of axitinib on NCC-BD1 (a gemcitabine-sensitive extra-hepatic cholangiocarcinoma cell line) and TKKK (a gemcitabine-resistant intra-hepatic cholangiocarcinoma cell line) using subcutaneous xenograft models.Oral administration of axitinib significantly inhibited the growth of TKKK xenografts at a dose of 6 mg kg(-1) day(-1) (P < 0.05), and the growth of NCC-BD1 xenografts at 30 mg kg(-1)day(-1) (P < 0.05). Treated tumors showed a significant decrease of microvessel density and the tumor cell proliferation index and a mild but significant increase of the apoptotic index in comparison with untreated tumors.Our results suggest that axitinib should be a promising therapy for vascular endothelial growth factor-expressing cholangiocarcinoma, irrespective of tumor origin and gemcitabine sensitivity.