Blansfield Joseph A, Caragacianu Diana, Alexander H Richard, Tangrea Michael A, Morita Shane Y, Lorang Dominique, Schafer Peter, Muller George, Stirling David, Royal Richard E, Libutti Steven K
Tumor Angiogenesis Section, Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2008 Jan 1;14(1):270-80. doi: 10.1158/1078-0432.CCR-07-1562.
Over the past 60 years, cytotoxic chemotherapy has targeted the cancer cell. Despite this, there have been few cancer cures. A new approach to cancer therapy is to target the multicellular biological entity of the tumor microenvironment.
Lenalidomide, an immunomodulatory drug, sunitinib, a tyrosine kinase inhibitor, and low-dose metronomic cyclophosphamide, were tested alone and in combination for their abilities to inhibit endothelial cell tube formation, rat aortic ring outgrowth, tumor growth, and metastatic development in mice. In addition, ectopic tumor lysates were evaluated for the presence of proangiogenic proteins.
The three agents alone were shown to significantly inhibit endothelial cells' ability to form tubes and significantly inhibit the multicellular microenvironment in the rat aortic ring assay (P < 0.01 and P < 0.001). This effect was also significantly augmented when the agents were combined. Furthermore, the three-drug combination was able halt the progression of tumor growth almost completely in xenograft models of ocular melanoma, colon cancer, pancreatic cancer, and cutaneous melanoma. These agents significantly decrease the number of proliferating cells in tumors, significantly increase the number of cells undergoing active cell death in tumors, and significantly decrease the number of blood vessels in treated tumors (P < 0.05). Combination therapy shows a decrease in the compensatory up-regulation of proangiogenic proteins after treatment when compared with single-agent therapy.
This combination of agents causes an inhospitable microenvironment for tumor cells and shows great promise for use in the clinic.
在过去60年里，细胞毒性化疗一直以癌细胞为靶点。尽管如此，癌症治愈的案例却很少。一种新的癌症治疗方法是针对肿瘤微环境的多细胞生物实体。
来那度胺（一种免疫调节药物）、舒尼替尼（一种酪氨酸激酶抑制剂）和低剂量节拍性环磷酰胺，分别单独及联合测试其抑制内皮细胞管形成、大鼠主动脉环生长、肿瘤生长以及小鼠转移发展的能力。此外，还评估了异位肿瘤裂解物中促血管生成蛋白的存在情况。
单独使用这三种药物均显示出能显著抑制内皮细胞形成管的能力，并在大鼠主动脉环试验中显著抑制多细胞微环境（P < 0.01和P < 0.001）。当这些药物联合使用时，这种效果也显著增强。此外，在眼部黑色素瘤、结肠癌、胰腺癌和皮肤黑色素瘤的异种移植模型中，三联药物组合几乎能完全阻止肿瘤生长的进程。这些药物显著减少肿瘤中增殖细胞的数量，显著增加肿瘤中发生主动细胞死亡的细胞数量，并显著减少治疗后肿瘤中的血管数量（P < 0.05）。与单药治疗相比，联合治疗显示治疗后促血管生成蛋白的代偿性上调有所减少。
这种药物组合为肿瘤细胞营造了一个不利的微环境，在临床应用中显示出巨大的前景。
