Mangiameli David P, Blansfield Joseph A, Kachala Stephan, Lorang Dominique, Schafer Peter H, Muller George W, Stirling David I, Libutti Steven K
Tumor Angiogenesis Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
J Transl Med. 2007 Jul 18;5:38. doi: 10.1186/1479-5876-5-38.
Ocular melanoma is the leading intraocular malignancy. There is no effective treatment for metastatic ocular melanoma. We sought a treatment targeting the tumor microenvironment as well as the tumor cells.
Migration of HUVEC cells, the ability of HUVEC cells to form tubes, and proliferative capacity of a human ocular melanoma cell line were tested in the presence of lenalidomide and sorafenib alone and in combination. The compounds were also tested in a rat aortic ring assay and were tested in a highly aggressive human ocular melanoma xenograft model.
Lenalidomide and Sorafenib inhibit HUVEC ability to migrate and form tubes and when used in combination the inhibition is increased. The agents alone and in combination inhibit outgrowth in the rat aortic ring model. The combination of the agents improved the inhibition over either single agent. In a xenograft model, combination therapy inhibited tumor growth over inhibition by single agent alone in a significant fashion (p < 0.004: lenalidomide and p < 0.0035: sorafenib). Furthermore, spontaneous lung metastasis development was completely inhibited in the combination treated animals. Sixty percent of vehicle treated animals developed lung metastases compared to 50% of lenalidomide treated animals, and 33% of sorafenib treated animals.
Lenalidomide and sorafenib are effective at targeting endothelial cells, inhibiting growth of ocular melanoma cells and can inhibit growth of tumors in a xenograft model as well as inhibit development of metastases. Combining these agents works in an additive to synergistic way to inhibit the growth of tumors and development of metastases.
眼黑色素瘤是主要的眼内恶性肿瘤。对于转移性眼黑色素瘤尚无有效的治疗方法。我们寻求一种既针对肿瘤微环境又针对肿瘤细胞的治疗方法。
在单独使用来那度胺和索拉非尼以及二者联合使用的情况下，测试人脐静脉内皮细胞（HUVEC）的迁移、形成管腔的能力以及一种人眼黑色素瘤细胞系的增殖能力。这些化合物还在大鼠主动脉环试验中进行了测试，并在高度侵袭性的人眼黑色素瘤异种移植模型中进行了测试。
来那度胺和索拉非尼抑制HUVEC迁移和形成管腔的能力，联合使用时抑制作用增强。单独使用和联合使用这些药物均抑制大鼠主动脉环模型中的血管生成。联合用药比单一用药的抑制作用更强。在异种移植模型中，联合治疗显著抑制肿瘤生长，其抑制作用超过单一药物单独使用时（来那度胺：p < 0.004；索拉非尼：p < 0.0035）。此外，联合治疗的动物完全抑制了自发性肺转移的发生。相比之下，接受赋形剂治疗的动物中有60%发生了肺转移，接受来那度胺治疗的动物中有50%发生了肺转移，接受索拉非尼治疗的动物中有33%发生了肺转移。
来那度胺和索拉非尼在靶向内皮细胞、抑制眼黑色素瘤细胞生长方面有效，并且在异种移植模型中可抑制肿瘤生长以及转移的发生。联合使用这些药物以相加至协同的方式抑制肿瘤生长和转移的发生。
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