PHARMACOKINETICS/PHARMACODYNAMICS OF ANTICANCER DRUGS IN CHILDHOOD SOLID TUMORS

儿童恶性实体瘤治疗失败可能是 与抗癌药物处置的可变性直接相关。 然而，患有癌症的儿童通常接受相同的药物剂量， 基于身体大小，不考虑药代动力学的可变性。 儿童临床药代动力学-药效学研究 通常是描述性的，而动物模型提供了更大的灵活性 在设计临床前假设检验研究方面。这个项目 重点是药代动力学/动力学方法学的应用 抗癌药物的量效关系研究 动物模型系统，并开发合理的药物治疗方案 儿童实体瘤的治疗，特别强调 喜树碱类似物。该项目的具体目标是：1) 建立喜树碱的准动力学-药效学关系 抗癌药物在人肿瘤移植瘤模型中的应用；2)测定 喜树碱在细胞外液中的浓度分布 异种移植物；3)阐明相关的潜在机制 与荷瘤小鼠相比，药物处置的改变 非荷瘤小鼠；4)建立药代动力学模型预测 喜树碱在脑脊液中的分布；以及5)确定最佳的 产生抗肿瘤活性的时间表和药代动力学暴露 给其他新特工。这些目标将主要通过 小鼠儿童肿瘤异种移植模型及在非人灵长类动物中的应用 表征药物的脑脊液处置情况。药物的型号 向细胞外液(ECF)的分布将被开发和 使用微透析法进行验证。在这个计划中， 浓度、曝光时间和曝光间隔 优化的细胞毒性将在体外表征。在这个项目中， 这些研究将利用独特的异种移植模型在体内进行扩展。 儿童实体瘤，以评估全身暴露，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 确定给药率或用药持续时间是否改变 分布在肿瘤组织中。将进行实验室研究 识别孕鼠体内药物代谢途径的改变 与正常小鼠进行比较。调查结果的翻译自 该项目将被纳入临床研究，以开发 最佳给药方案，并验证在 动物模型。

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.