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

开发 CES 2 激活的多恶唑烷前药用于治疗胰腺癌

基本信息

批准号：
7707826
负责人：
TAD H KOCH
金额：
$ 21.06万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7707826
关键词：
ABCB1 gene Acylation Address Adult Adverse effects Alanine Transaminase Albumins Alpha-hydroxybutyrate dehydrogenase Anthracyclines Antineoplastic Protocols Aspartate Transaminase Autopsy Back Binding Biological Biological Markers Blood Blood specimen Body Weight Body Weight Changes Camptothecin Cancer Etiology Carbamates Carbonates Carboxylic Ester Hydrolases Cardiac Myocytes Cardiotoxicity Cell Death Cells Cessation of life Cleaved cell Cysteine Cytotoxic agent Detection Developed Countries Development Diagnosis Disease Resistance Doxorubicin Drug Delivery Systems Drug Formulations Environment Evaluation Fluorescence Fluorescence Microscopy Formaldehyde Growth Heart Hepatotoxicity High Pressure Liquid Chromatography Histopathology Human Hydrazones In Vitro Injection of therapeutic agent Ketones Kinetics Lactate Dehydrogenase Liposomes Literature Liver Lung Lysosomes MCF7 cell Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of pancreas Malondialdehyde Mass Spectrum Analysis Measures Methodology Modeling Monitor Mus Nitric Oxide Non-Small-Cell Lung Carcinoma Northern Blotting Nucleosides Nude Mice Organ Pancreas Permeability Personal Satisfaction Pharmaceutical Preparations Phase I Clinical Trials Phase II Clinical Trials Phenotype Plasma Population Positioning Attribute Process Prodrugs Protocols documentation Rattus Reaction Relative (related person)Renal carcinoma Research Resistance Sampling Signal Transduction Specificity Specimen Staging Structure Time Tissues Toxic effect Vacuole Vascular System Wistar Rats Work Xenograft Model Xenograft procedure analytical tool base cancer cell cancer therapy carboxylesterase cell growth crosslink cytotoxic design drug metabolism extracellular functional group gemcitabine in vivo inhibitor/antagonist intravenous administration irinotecan late endosome male mouse model neoplastic cell overexpression oxazolidine pancreatic neoplasm paraform pre-clinical preclinical evaluation public health relevance research study resistance mechanism response subcutaneous therapeutic target tumor tumor growth

项目摘要

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.

描述（由申请人提供）：胰腺癌是与癌症相关死亡的最常见原因之一，尽管其发生相对较低，因此仍需要新的疗法，尤其是解决抗药性的疗法。提出了研究以评估体内一种新设计的，有针对性的，针对性的前药治疗，该癌症过表达羧酸酯酶CES2，重点是胰腺癌。该疗法基于罗唑啉（Doxazolidine），黄唑啉是阿霉素的甲醛结合物，它比对多种敏感和抗性（MDR表型）癌细胞的活性更高，而不是阿霉素。黄唑啉通过不同的机制诱导癌细胞死亡，对心肌细胞的毒性比阿霉素较小。 doxazolidine，n-（氯乙烯甲苄酰基-P-氨基苯甲酰氧甲苯甲苯甲苯甲苯）doxazolidine（pentyl pabc- doxaz，ppd），在胰腺，肝脏，肺癌和肾脏癌细胞中被CES2激活。该药物不活跃，直到被CES2裂解。对特异性至关重要的是人血浆中预测血管系统稳定性的稳定性。该疗法旨在最大程度地提高功效并最大程度地减少包括心脏毒性在内的副作用。在大鼠心肌细胞中表达的CES2很少，而前药对大鼠心肌细胞的毒性比阿霉素低两个数量级。还提出了一种使用增强的渗透性和保留率（EPR）效应的药物输送策略，以最大程度地提高功效并最大程度地减少副作用。实验旨在评估胰腺癌的原位小鼠模型中的治疗，并评估全身毒性，包括大鼠模型中的有氧运动和肝毒性。使用表达CES2的癌细胞，初步皮下异种移植实验表明肿瘤的生长抑制作用，没有明显的副作用，而无明显的副作用。公共卫生相关性：胰腺癌是西方工业化国家最常见的与癌症相关死亡的原因之一（9至10例 / 100,000例 / 100,000例），因为它在早期阶段通常是无症状的，并且在后期阶段诊断时具有侵略性，转移性和抵抗力。提出了研究来评估体内一种新设计的针对胰腺癌的靶向治疗方法，该治疗应有效防止转移性和抗性疾病，其副作用最少。