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 通常是描述性的，而动物模型提供了更大的灵活性 设计临床前假设检验研究。 这个项目 侧重于药代动力学/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， 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） 喜树碱药动学-药效学关系研究 抗癌药物在人肿瘤异种移植模型中的作用; 2）确定 细胞外液（ECF）中喜树碱的浓度分布 异种移植物; 3）阐明负责的潜在机制 在荷瘤小鼠中的药物处置改变， 非荷瘤小鼠; 4）开发药代动力学模型以预测 喜树碱在CSF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 其他新代理商。 这些目标将主要通过 小鼠儿科肿瘤异种移植物模型和非人灵长类动物中， 表征药物的脑脊液处置。 药物模型 将开发细胞外液（ECF）的分布， 使用微透析方法进行验证。 在该计划中， 浓度、暴露时间和暴露之间的间隔， 优化的细胞毒性将在体外表征。 在这个项目中， 这些研究将使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 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 以确定在小鼠中改变的药物代谢途径， 与正常小鼠相比，异种移植物。 翻译的结果， 该项目将纳入临床研究， 最佳给药方案，并验证 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.