Development of a CES 2-Activated Doxazolidine Prodrug for Pancreatic Cancer

描述（由申请人提供）：胰腺癌是癌症相关死亡的最常见原因之一，尽管其发生率相对较低，但需要新的治疗方法，特别是解决耐药性的治疗方法。研究拟在体内评估一种新设计的、靶向的前药疗法，用于过表达羧酸酯酶CES 2的癌症，重点是胰腺癌。该疗法基于多唑烷，多柔比星的甲醛缀合物，其对多种敏感和耐药（MDR表型）癌细胞的活性比多柔比星高一个数量级以上。多恶唑烷通过不同的机制诱导癌细胞死亡，并且对心肌细胞的毒性低于阿霉素。多沙唑烷的前药，N-（戊氧基羰基-对氨基苄氧基羰基）多沙唑烷（戊基PABC-Doxaz，PPD），在胰腺癌、肝癌、肺癌和肾癌细胞以及其他癌细胞中被CES 2活化。该药物在被CES 2裂解前无活性。特异性的关键是人血浆中的稳定性，可预测血管系统中的稳定性。该疗法旨在最大限度地提高疗效并最大限度地减少副作用，包括心脏毒性。在大鼠心肌细胞中表达非常少的CES 2，并且前药对大鼠心肌细胞的毒性比阿霉素低两个数量级。还提出了利用增强的渗透性和保留（EPR）效应的药物递送策略，以最大化功效并最小化副作用。设计实验以在胰腺癌的原位小鼠模型中评价治疗，并在大鼠模型中评价全身毒性，包括心脏和肝脏毒性。初步的皮下异种移植实验表明，在使用表达CES 2的癌细胞的肝癌和非小细胞肺癌小鼠模型中，肿瘤生长受到抑制，且没有显着的副作用。公共卫生相关性：胰腺癌是西方工业化国家癌症相关死亡的最常见原因之一（9至10例/100，000人口），因为它通常在早期阶段无症状，在后期诊断时具有侵袭性、转移性和耐药性。研究拟在体内评估一种新设计的胰腺癌靶向治疗药物，该药物应能有效对抗转移性和耐药性疾病，副作用最小。

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most common causes of cancer-related deaths in spite of its relatively low occurrence, and new therapies are needed, especially ones that address resistance. Research is proposed to evaluate in vivo a newly designed, targeted, prodrug therapy for cancers that overexpress the carboxylesterase, CES2, with focus on pancreatic cancer. The therapy is based upon doxazolidine, a formaldehyde conjugate of doxorubicin that is more than an order of magnitude more active against a variety of both sensitive and resistant (MDR phenotype) cancer cells than doxorubicin. Doxazolidine induces cancer cell death by a different mechanism and is less toxic to cardiomyocytes than doxorubicin. The prodrug of doxazolidine, N-(pentyloxycarbonyl-p-aminobenzyloxycarbonyl)doxazolidine (pentyl PABC- Doxaz, PPD), is activated by CES2 in pancreas, liver, lung and kidney cancer cells amongst other cancer cells. The drug is inactive until cleaved by CES2. Critical to specificity is stability in human plasma predicting stability in the vascular system. The therapy is designed to maximize efficacy and minimize side effects including cardiotoxicity. Very little CES2 is expressed in rat cardiomyocytes and the prodrug is two orders of magnitude less toxic to rat cardiomyocytes than doxorubicin. A drug delivery strategy that utilizes enhanced permeability and retention (EPR) effect is also proposed to maximize efficacy and minimize side effects. Experiments are designed to evaluate the therapy in an orthotopic mouse model of pancreatic cancer and to evaluate systemic toxicity including cardio and liver toxicity in a rat model. Preliminary subcutaneous xenograft experiments indicate tumor growth inhibition without significant side effects in mouse models of liver cancer and non-small cell lung cancer using cancer cells that express CES2. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is one of the most frequent causes of cancer-related deaths in Western industrialized countries (9 to 10 cases / 100,000 population) because it is often asymptomatic at early stages and aggressive, metastatic, and resistant upon diagnosis at later stages. Research is proposed to evaluate in vivo a newly designed, targeted therapeutic for pancreatic cancer that should be effective against metastatic and resistant disease with minimal side effects.