Plasmin-activated Prodrug Therapy for Pancreatic Cancer

纤溶酶激活的前药治疗胰腺癌

• 批准号: 7161267
• 负责人: DAVID Jay BURKHART
• 金额: $ 10万
• 依托单位: SERENDIPITY PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7161267
• 关键词: model; neoplasm /cancer; neoplastic cell; pancreas neoplasms; plasmin; prodrugs

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer related deaths and the median survival time after diagnosis is only 5 months. The disease is generally metastatic with limited treatment options. Research is proposed to evaluate in vivo a newly designed, targeted, prodrug therapy for pancreatic cancer that should be effective against metastatic and resistant disease. The therapy is based upon the active metabolite of the antitumor drug doxorubicin, which is an order of magnitude more active against pancreatic cancer cells than doxorubicin and is active against a wide variety of both sensitive and resistant cancer cells. Targeting is achieved through activation by the enzyme plasmin, overexpressed by many cancer cells, including pancreatic cancer cells, and their associated angiogenesis. The drug is inactive until cleaved by plasmin that is created at the cell surface by hydrolysis of plasminogen. Critical to specificity is inactivation of plasmin that escapes to the vascular system by circulating antiplasmins. The therapy is designed to maximize efficacy and minimize side effects including cardiotoxicity. Experiments are proposed to evaluate the therapy in a nude mouse model of pancreatic cancer and to evaluate systemic toxicity including cardiotoxicity in a rat model.

描述（由申请人提供）：胰腺癌是癌症相关死亡的第四大原因，诊断后的中位生存时间仅为 5 个月。该疾病通常是转移性的，治疗选择有限。拟议的研究旨在评估一种新设计的、针对胰腺癌的靶向前药疗法，该疗法应能有效对抗转移性和耐药性疾病。该疗法基于抗肿瘤药物阿霉素的活性代谢物，它对胰腺癌细胞的活性比阿霉素高一个数量级，并且对多种敏感和耐药癌细胞都有活性。靶向是通过纤溶酶的激活来实现的，纤溶酶在许多癌细胞（包括胰腺癌细胞）及其相关的血管生成中过度表达。该药物在被纤溶酶原水解在细胞表面产生的纤溶酶裂解之前呈惰性。特异性的关键是纤溶酶的失活，纤溶酶通过循环抗纤溶酶逃逸到血管系统。该疗法旨在最大限度地提高疗效并最大限度地减少包括心脏毒性在内的副作用。建议进行实验来评估胰腺癌裸鼠模型中的治疗，并评估大鼠模型中的全身毒性，包括心脏毒性。