Effects of putative hydroxylated thalidomide metabolites on blood vessel density in the chorioallantoic membrane (CAM) assay and on tumor and endothelial cell proliferation
Effects of putative hydroxylated thalidomide metabolites on blood vessel density in the chorioallantoic membrane (CAM) assay and on tumor and endothelial cell proliferation
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DOI：
10.1248/bpb.25.597
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发表时间：
2002-05-01
影响因子：
2
通讯作者：
Li, PK
中科院分区：
文献类型：
--
作者：
Marks, MG;Shi, JD;Li, PK
血管生成，特别是抗血管生成，是癌症治疗中特别有治疗意义的领域。几种抗血管生成剂正处于临床试验的最后阶段。这些药物之一，沙利度胺，最有名的是其致畸潜力，显示出对几种肿瘤类型的承诺。沙利度胺之前已显示需要生物活化以在分离的血管和内皮细胞中发挥其抗血管生成作用。在这项工作中，我们证实了这些发现使用子宫内鸡胚绒毛尿囊膜（CAM）系统。特别是，沙利度胺的抗血管生成作用显着增强激活的人，但不是由大鼠肝微粒体。我们还在CAM测定中表明，沙利度胺在1 '-或5-位的羟基化保留了抗血管生成活性，而其在4-位的羟基化导致无活性化合物。我们进一步证明了沙利度胺对培养的MDA-MB-231人乳腺癌细胞显示出弱的抗增殖活性。然而，沙利度胺对SH-SY 5 Y人神经母细胞瘤和人脐静脉内皮细胞（HUVEC）类型显示出略高的抗增殖活性。此外，与沙利度胺单独给药相比，沙利度胺与人肝微粒体孵育在这些细胞类型中没有增加额外的抗增殖作用。最后，我们报告说，没有沙利度胺代谢产物测试有任何抗增殖作用对乳腺癌或神经母细胞瘤细胞，但具有明显的抗增殖活性对内皮细胞。总之，这项工作表明，羟基化沙利度胺类似物的基础上推定的代谢产物的药物具有显着的抗血管生成活性，并探索进一步的衍生物，这些作为潜在的抗血管生成剂值得进一步的价值。
Angiogenesis, in particular anti-angiogenesis, is an area of particular therapeutic interest in cancer treatment. Several anti-angiogenic agents are in the final stages of clinical trials. One of these agents, thalidomide, best known for its teratogenic potential, is showing promise against several tumor types. Thalidomide has been shown previously to require bio-activation to exert its anti-angiogenic effect in isolated blood vessels and endothelial cells. In this work, we confirmed these findings using the in utero chicken embryo chorioallantoic membrane (CAM) system. In particular, the anti-angiogenic effect of thalidomide is significantly enhanced by activation by human but not by rat liver microsomes. We also showed in the CAM assay that hydroxylation of thalidomide at either the 1'- or 5-position retained anti-angiogenic activity whereas its hydroxylation at the 4-position led to an inactive compound. We further demonstrated that thalidomide shows weak anti-proliferative activity against MDA-MB-231 human breast cancer cells in culture. Thalidomide showed slightly more anti-proliferative activity, however, against the SH-SY5Y human neuroblastoma and human umbilical vein endothelial cell (HUVEC) types. Furthermore, incubation of thalidomide with human liver microsomes added no additional anti-proliferative effect in these cell types versus thalidomide given alone. Finally, we report that none of the thalidomide metabolites tested had any anti-proliferative effect against the breast or neuroblastoma cells, but do possess appreciable anti-proliferative activity against the endothelial cells. In summary, this work suggests that hydroxylated thalidomide analogs based on putative metabolites of the drug possess significant anti-angiogenic activity and that exploring further derivatives of these as potential anti-angiogenic agents warrants further merit.