(PQD5) imaging systemic tissue injuries induced by anticancer drugs

(PQD5)抗癌药物引起的全身组织损伤成像

• 批准号: 8687127
• 负责人: Andrew P Mazar
• 金额: $ 48.83万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-07 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687127
• 关键词: Acute; Adverse effects; Affinity; Amino Acids; Antibodies; Antineoplastic Agents; Apoptosis; Binding; Biodistribution; Biological Markers; Categories; Cell Death; Cell membrane; Cells; Chronic; Cisplatin; Clinical Oncology; Clinical Trials; Collaborations; Development; Diagnostic; Diffuse; Discipline of Nuclear Medicine; Dose; Doxorubicin; Drug Combinations; Drug Tolerance; Evaluation; Goals; Gold; Human; Image; Imaging Techniques; Individual; Injury; Kinetics; Longitudinal Studies; Measurement; Modeling; Molecular; Necrosis; Noise; Normal tissue morphology; Organ; Outcome; Paclitaxel; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phosphatidylethanolamine; Population; Predisposition; Preparation; Process; Prognostic Marker; Radiation; Radiopharmaceuticals; Rattus; Regimen; Rodent Model; Roentgen Rays; Running; Scanning; Signal Transduction; Specificity; Surveys; Therapeutic; Tissues; Toxic effect; Toxicology; Toxin; Translating; Translations; Universities; anticancer treatment; base; cancer therapy; chemotherapy; clinically relevant; drug candidate; drug development; drug discovery; duramycin; experience; improved; in vivo; indexing; innovation; irinotecan; irradiation; killings; meetings; neoplastic cell; novel strategies; oncology; polypeptide; prognostic; public health relevance; response; tumor; uptake; validation studies; whole body imaging

Chemotherapeutic drugs are toxins for killing tumor cells, but their efficacy is often limited by the tolerance ceiling of normal tissues. A survey of systemic toxicity will provide valuable information on a new drug candidate for pharmaceutical development, and on the therapeutic regimen for existing drug combinations for each patient. The overall goal of this project is to develop and validate whole-body apoptosis imaging as a new approach for characterizing the systemic toxicity profile of anticancer drugs. Apoptosis is an important manifestation of toxicity-induced tissue injuries. A whole-body scan, which we call "ToxScan", detects tissue injuries systemically, in terms of a toxicity profile in response to the drug. We use a radiopharmaceutical, 99mTc-Duramycin, which detects exposed phosphatidylethanolamine in dead and dying cells. The imaging agent has binding affinity/specificity like an antibody yet clearance kinetics of a peptide. It is thus uniquely suited for whole-body imaging applications. Our central hypothesis is that a systemic toxicity profile reflects the individual susceptibility to anticancer treatment. The scan provides indices for drug tolerance, and a prognostic indicator for chronic adverse effects. In preliminary studies, we demonstrated the sensitivity of whole-body 99mTc-Duramycin scan by detecting cell death in multiple tissues after a single clinically relevant dose of Doxorubicin. Whole-body apoptosis scan also revealed individualized response to the same therapeutic regimen. Single- and multi-organ indices for tissue injury are being derived for diagnostic and prognostic purposes. The evaluation of toxicity in such fashion will significantly accelerate the development of new anticancer drugs and new combination treatments. Ultimately, this approach will benefit oncology patients by optimizing therapies on a personalized basis.

化疗药物是杀死肿瘤细胞的毒素，但其疗效往往受到耐受性的限制 正常组织的天花板。对全身毒性的调查将提供有关新药的有价值的信息 药物开发的候选者，以及现有药物组合的治疗方案 每一位病人。该项目的总体目标是开发和验证全身细胞凋亡成像作为一种新的 抗癌药物全身性毒性图谱的表征方法。细胞凋亡是一个重要的 毒性引起的组织损伤的表现。全身扫描，我们称之为“ToxScan”，检测组织 系统性伤害，就药物反应的毒性情况而言。我们使用一种放射性药物， 99mTc-杜拉霉素，检测死亡和濒死细胞中暴露的磷脂酰乙醇胺。成像 试剂具有抗体一样的结合亲和力/特异性，但又具有多肽的清除动力学。因此它是独一无二的 适用于全身成像应用。我们的中心假设是，全身毒性特征反映了 个体对抗癌治疗的敏感性。扫描提供了药物耐受性的指标，并提供了预后 慢性不良反应的指标。在初步研究中，我们展示了全身的敏感性 单次临床相关剂量的99mTc-杜拉霉素扫描检测多个组织的细胞死亡 阿霉素。全身细胞凋亡扫描也显示了对相同治疗的个性化反应 养生法。组织损伤的单器官和多器官指数正被用于诊断和预后 目的。以这种方式评估毒性将极大地促进新技术的发展 抗癌药物和新的联合治疗。最终，这种方法将使肿瘤学患者受益于 在个性化的基础上优化治疗。