Angiocidal Effect of Cyclosporine in Cancer Therapy

描述(由申请人提供)： 我们的应用代表了肿瘤学和移植之间的交叉受精，在癌症的治疗中使用环孢素A(CyA)作为抗血管生成剂。抗血管生成药物在癌症治疗中是很有前景的辅助药物，但其潜力尚未完全实现，部分原因是这些药物缺乏强大的血管杀灭作用。 我们在小鼠血管生成模型中的初步数据表明，CyA具有血管杀灭作用，这表明CyA可能是一种潜在的癌症治疗中的抗血管生成剂。我们的数据还表明，大剂量环磷酰胺的毒性主要是由于内皮素-1(ET-1)的过度释放，并可通过阻断平滑肌和心肌细胞上的ET-1A受体来防止。 我们的假设是，大剂量的CyA会由于内皮细胞氧化应激的增加而破坏肿瘤的血管生成，导致VE-cadherin的重新分布和内皮细胞与细胞之间的接触丧失。我们建议在小鼠的肉瘤异种移植模型和黑色素瘤同种移植癌模型中，通过单独应用大剂量环磷酰胺并与常规化疗药物联合使用来验证这一假说。将在这些小鼠中监测肿瘤生长、血管生成和药物毒性，以确定环磷酰胺在癌症治疗中是否与化疗药物协同作用。 我们的研究有可能发现一种常用药物的新的血管杀灭作用。如果成功，这些研究将很快转化为癌症治疗的临床试验。

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.