Angiocidal Effect of Cyclosporine in Cancer Therapy

环孢素在癌症治疗中的杀血管作用

• 批准号: 7031611
• 负责人: DILIP S KITTUR
• 金额: $ 12.76万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-14 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031611
• 关键词: angiogenesis; cyclosporines; drug screening /evaluation; laboratory mouse; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; neoplastic growth; nonhuman therapy evaluation; sarcoma; xenotransplantation

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.

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，利用环孢菌素 A (CyA) 作为癌症治疗中的抗血管生成剂。抗血管生成剂是癌症治疗中很有前途的辅助剂，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伤作用。 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 可能是癌症治疗中潜在的抗血管生成剂。我们的数据还表明，高剂量 CyA 的毒性（该药物具有杀血管作用）主要是由于内皮素-1 (ET-1) 的过量释放所致，并且可以通过阻断平滑肌和心肌细胞上的 ET-1A 受体来预防。 我们的假设是，高剂量 CyA 会破坏肿瘤中的血管生成，因为内皮细胞氧化应激增加，导致 VE-钙粘蛋白重新分布和内皮细胞与细胞接触的丧失。我们建议通过单独施用高剂量 CyA 以及与常规化疗剂联合施用，在小鼠癌症的肉瘤异种移植模型和黑色素瘤同种移植模型中检验这一假设。将监测这些小鼠的肿瘤生长、血管生成和药物毒性，以确定 CyA 是否与化疗药物在癌症治疗中具有协同作用。 我们的研究有可能发现一种常用药物的新颖的血管杀伤作用。如果成功，这些研究将迅速转化为治疗癌症的临床试验。

项目成果

An interleukin-6-neutralizing antibody prevents cyclosporine-induced nephrotoxicity in mice.

白细胞介素 6 中和抗体可预防环孢菌素诱导的小鼠肾毒性。

• DOI: 10.1016/j.jss.2007.12.786
• 发表时间: 2008
• 期刊: The Journal of surgical research
• 作者: LaSpina,Mark;Tripathi,Sudipta;Gatto,LouisA;Bruch,David;Maier,KristopherG;Kittur,DilipS
• 通讯作者: Kittur,DilipS