Determinants for in vivo antitumor effect of angiogenesis inhibitor SU5416 formulated in PEGylated emulsion.
Determinants for in vivo antitumor effect of angiogenesis inhibitor SU5416 formulated in PEGylated emulsion.
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DOI：
10.1002/jps.24071
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发表时间：
2014-08
影响因子：
3.8
通讯作者：
K. Ogawara;Shigeki Abe;K. Un;Yuta Yoshizawa;Toshikiro Kimura;K. Higaki
中科院分区：
文献类型：
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作者：
K. Ogawara;Shigeki Abe;K. Un;Yuta Yoshizawa;Toshikiro Kimura;K. Higaki
血管生成，即毛细血管从先前存在的毛细血管中发芽，对于实体瘤的持续生长至关重要。在这项研究中，我们使用SU5416（一种疏水分子，具有强效的血管内皮生长因子（VEGF） 2型受体酪氨酸激酶抑制剂）作为聚乙二醇化乳剂（SU5416- pe），并在Lewis肺癌（LLC）、结肠癌-26 （C26）和B16BL6黑色素瘤（B16）荷瘤小鼠中评估了该制剂的抗肿瘤效力。荷瘤小鼠静脉注射SU5416-PE可显著抑制C26和B16肿瘤的生长，但对LLC肿瘤的生长无影响。MTT实验显示，SU5416对人脐静脉内皮细胞的增殖有浓度依赖性的抑制作用，但对所有类型的肿瘤细胞均没有这种抑制作用，说明SU5416对内皮细胞具有特异性。考虑到C26和B16肿瘤中VEGF水平分别比LLC肿瘤高约10倍和20倍，我们认为SU5416-PE会抑制C26和B16等肿瘤组织的血管生成，其中VEGF在促进血管生成中起主要作用，从而抑制体内肿瘤生长。
Angiogenesis, the sprouting of capillaries from preexisting ones, is essential for the sustained growth of solid tumors. In this study, we used SU5416, a hydrophobic molecule with potent tyrosine kinase inhibitor of type 2 receptor for vascular endothelial growth factor (VEGF), as PEGylated emulsion (SU5416-PE), and evaluated the antitumor potency of this formulation in Lewis lung cancer (LLC), Colon-26 (C26), and B16BL6 melanoma (B16) tumor-bearing mice. Intravenous injection of SU5416-PE into tumor-bearing mice significantly suppressed the growth of C26 and B16 tumors, but had no effect on the growth of LLC tumors. MTT assay revealed that SU5416 inhibited the proliferation of human umbilical vein endothelial cells in a concentration-dependent manner but did not show such an inhibitory effect on all types of tumor cells examined, demonstrating the specificity of SU5416 for endothelial cells. Considering that VEGF levels within C26 and B16 tumors were found to be about 10-fold and 20-fold higher than that in LLC tumors, respectively, it was suggested that SU5416-PE would inhibit angiogenesis in certain types of tumor tissue such as C26 and B16 where VEGF plays a major role for promoting angiogenesis, leading to the suppression of in vivo tumor growth.