Angiocidal Effect of Cyclosporine in Cancer Therapy

描述（由申请人提供）： 我们的申请代表了肿瘤学和移植之间的交叉受精，利用环孢菌素A（CyA）作为抗血管生成剂治疗癌症。抗血管生成剂在癌症治疗中是有前途的药物，但其潜力尚未完全实现，部分原因是这些药物缺乏强的杀血管作用。 我们在小鼠血管生成模型中的初步数据表明，CyA具有杀血管作用，这表明CyA可能是一种潜在的抗血管生成剂在癌症治疗中。我们的数据还表明，高剂量CyA的毒性，在该药物是杀血管的，主要是由于过量释放的内皮素-1（ET-1），并通过阻断ET-1A受体对平滑肌和心肌细胞。 我们的假设是，高剂量CyA将破坏肿瘤中的血管生成，这是由于内皮细胞氧化应激的增加导致VE-钙粘蛋白的重新分布和内皮细胞-细胞接触的丧失。我们建议通过单独施用高剂量CyA和与常规化疗剂组合施用高剂量CyA来在小鼠中的肉瘤异种移植模型和癌症的黑素瘤同种移植模型中测试这一假设。将在这些小鼠中监测肿瘤生长、血管生成和药物毒性，以确定CyA是否在癌症治疗中与化疗剂协同作用。 我们的研究有可能发现一种新的常用药物的杀血管作用。如果成功，这些研究将迅速转化为治疗癌症的临床试验。

DESCRIPTION (provided by applicant): Our application represents a cross fertilization between oncology and transplantation by utilizing cyclosporin A (CyA) as an antiangiogenic agent in the treatment of cancers. Antiangiogenic agents are promising adjuncts in cancer therapy, but their potential has not been fully realized, partly due to a lack of a strong angiocidal effect of these drugs. Our preliminary data in a mouse model of angiogenesis indicates that CyA has angiocidal effects, suggesting that CyA could be a potential antiangiogenic agent in cancer therapy. Our data also indicates that the toxicity of high dose CyA, at which the drug is angiocidal, is principally due to an excess release of Endothelin-1 (ET-1) and is prevented by blockade of the ET-1A receptor on smooth muscle and myocardial cells. Our hypothesis is that high dose CyA will disrupt angiogenesis in tumors due to increase in endothelial cell oxidative stress leading to redistribution of VE-cadherin and loss of endothelial cell-cell contacts. We propose to test this hypothesis in a sarcoma xenograft model and a melanoma isograft model of cancer in mice by administering high dose CyA alone and in combination with a conventional chemotherapeutic agent. Tumor growth, angiogenesis, and drug toxicity will be monitored in these mice to determine if CyA synergizes with the chemotherapeutic agent in the treatment of cancer. Our studies have the potential of discovering a novel, angiocidal effect of a commonly used drug. If successful, these studies will be translated expeditiously into clinical trials for the treatment of cancer.