PHARMACOKINETICS/PHARMACODYNAMICS OF ANTICANCER DRUGS IN CHILDHOOD SOLID TUMORS

抗癌药物在儿童实体瘤中的药代动力学/药效学

• 批准号: 6500719
• 负责人: WILLIAM R CROM
• 金额: $ 28.58万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6500719
• 关键词: Macaca mulatta; antineoplastics; camptothecin; cerebrospinal fluid; clinical research; cytotoxicity; disease /disorder model; dosage; drug administration rate /duration; extracellular matrix; human tissue; laboratory mouse; medulloblastoma; microdialysis; model design /development; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neuroblastoma; pediatric neoplasm /cancer; pharmacokinetics; rhabdomyosarcoma

Treatment failure in children with malignant solid tumors may be directly related to variability in anticancer drug disposition. However, children with cancer usually receive identical drug dosages, based on body size, without accounting for pharmacokinetic variability. Clinical pharmacokinetic-pharmacodynamic investigations in children are ofter descriptive, while animal models provide greater flexibility in designing preclinical hypothesis-testing studies. This project focuses on the application of pharmacokinetic/dynamic methodologies to characterize concentration-effect relationships of anticancer drugs in animal model systems, and to develop rational drug therapy regimens for the treatment of children with solid tumors, with particular emphasis on camptothecin analogs. The specific aims of this project are: 1) to establish parmacokinetic-pharmacodynamic relationships of camptothecin anticancer drugs in human tumor xenograft models; 2) to determine the concentration profile of camptothecins in the extracellular fluid (ECF) of xenografts; 3) to elucidate the underlying mechanisms responsible for altered drug disposition in tumor-bearing mice compared to nontumor-bearing mice; 4) to develop a pharmacokinetic model to predict disposition of camptothecins in the CSF; and 5) to identify the optimal schedules and pharmacokinetic exposures producing antitumor activity for other new agents. These aims will be addressed primarily with the murine pediatric tumor xenograft model and in nonhuman primates to characterize cerebrospinal fluid disposition of drugs. Models of drug distribution into extracellular fluid (ECF) will be developed and validated using microdialysis methods. Within this program, the concentrations, exposure times, and intervals between exposures that optimize cytotoxicity will be characterized in vitro. In this project, these studies will be extended in vivo, using unique xenograft models of childhood solid tumors, to evaluate systemic exposure, tissue exposure, and tumor responses, and to construct pharmacodynamic models for clinical use. Studies of ECF and plasma drug concentrations will determine whether rates or duration of drug administration alter distribution into tumor tissues. Laboratory studies will be undertaken to identify altered drug metabolism pathways in mice bearing xenographs, compared to normal mice. Translation of the findings from this project will be incorporated into clinical studies to develop optimal dosing regimens and to verify the relatonships identified in the animal models.

儿童恶性实体瘤治疗失败的原因可能是 与抗癌药物处置的变异性直接相关。 然而，患有癌症的儿童通常接受相同的药物剂量， 基于体型，不考虑药代动力学变异性。 儿童临床药代动力学-药效学研究 通常具有描述性，而动物模型则提供更大的灵活性 设计临床前假设检验研究。 这个项目 专注于药代动力学/动力学方法的应用 表征抗癌药物的浓度-效应关系 动物模型系统，并制定合理的药物治疗方案 治疗患有实体瘤的儿童，特别强调 喜树碱类似物。 该项目的具体目标是：1） 建立喜树碱的药代动力学-药效关系 人类肿瘤异种移植模型中的抗癌药物； 2）确定 细胞外液 (ECF) 中喜树碱的浓度分布 异种移植物； 3）阐明潜在的机制 与相比，荷瘤小鼠的药物配置发生了改变 非荷瘤小鼠； 4）建立药代动力学模型进行预测 喜树碱在脑脊液中的处置； 5) 确定最优的 产生抗肿瘤活性的时间表和药代动力学暴露 对于其他新代理。 这些目标将主要通过 小鼠小儿肿瘤异种移植模型和非人灵长类动物 表征药物的脑脊液分布。 药物模型 将开发和分配到细胞外液（ECF）中 使用微透析方法进行验证。 在此计划内， 浓度、暴露时间和暴露间隔 优化细胞毒性将在体外进行表征。 在这个项目中， 这些研究将使用独特的异种移植模型在体内扩展 儿童实体瘤，评估全身暴露、组织 暴露和肿瘤反应，并构建药效学模型 供临床使用。 ECF 和血浆药物浓度的研究将 确定给药速率或持续时间是否改变 分布到肿瘤组织中。 将进行实验室研究 鉴定小鼠体内药物代谢途径的改变 异种移植图，与正常小鼠相比。 调查结果的翻译 该项目将纳入临床研究以开发 最佳给药方案并验证中确定的关系 动物模型。