PHASE I MOLECULAR AND CLINICAL PHARMACODYNAMIC TRIALS

描述：（申请人的描述）本提案的目的是 开发新的，基于实验室的化疗治疗策略， 在第一阶段的应用。 这些第一阶段的研究将不会导致 仅涉及最大耐受剂量的分配和理解 特异性毒剂的正常组织毒性谱 它针对新的分子途径，但也将提供一种机制， 评价药物对关键肿瘤细胞功能的影响。 这一目标将由一组分子药理学家追求， 来自两个NCI指定的癌症中心和一个大型 大学医院谁将使用广泛的实验室和病人 希望之城国家医疗中心（COH），肯尼斯 小诺里斯南方大学综合癌症中心 加州（南加州大学）和加州大学戴维斯分校癌症中心， 进行I期分子药效学研究，重点是：1）新型 显著改变DNA甲基化模式的化合物或直接 抑制DNA甲基转移酶作为一种独特的酶的活性 活性; 2）在细胞周期中产生关键改变的新试剂 检查点控制或细胞周期进程作为其作用机制; 3)药物浓度（而不是剂量）在 剂量密集化疗的疗效和毒性以及效果 器官功能异常对药代动力学和药效学的影响 癌症治疗评估中可获得的新抗肿瘤药物 NCI的计划;和4）新的杀虫剂的识别 可从NCI的癌症治疗评估计划获得;以及4） 治疗活性和药物新分子相关物的鉴定 耐药性，包括DNA损伤，修复和甲基化的新标记， 对于具有新作用机制的化合物，以及紫杉烷， 铂、抗代谢药和拓扑异构酶I类药物。 基于 患者增加的重要记录以及实质性临床， 生物统计学和实验室相互作用在过去三年 这为一套新的拟议的第一阶段提供了理论基础， 试验，COH，USC和UCD的研究人员非常适合快速 完成抗癌药物的药理学驱动的I期试验 靶向关键的新细胞内通路。

DESCRIPTION: (Applicant's Description) The objective of this proposal is to develop new, laboratory-based chemotherapeutic treatment strategies for application in the phase I setting. These phase I studies will lead not only to the assignment of a maximum tolerated dose and to an understanding of the spectrum of normal tissue toxicity for specific antineoplastic agents that target novel molecular pathways, but will also provide a mechanistic evaluation of the effects of the agents on critical tumor cell functions. This objective will be pursued by a group of molecular pharmacologists and clinical scientists from two NCI-designated Cancer Centers and a large University Hospital who will use the extensive laboratory and patient resources of the City of Hope National Medical Center (COH), the Kenneth Norris, Jr. Comprehensive Cancer Center at the University of Southern California (USC), and the University of California, Davis Cancer Center to perform phase I molecular pharmacodynamic studies that focus on: 1) novel compounds which significantly modify patterns of DNA methylation or directly inhibit the activity of DNA methyltransferase as a unique antineoplastic activity; 2) new agents which produce critical alterations in cell cycle checkpoint control or cell cycle progression as their mechanism of action; 3) the role of antineoplastic drug concentration (rather than dose) in the efficacy and toxicity of dose-intensive chemotherapy, as well as the effects of abnormal organ function on the pharmacokinetics and pharmacodynamics of new antineoplastic agents available from the Cancer Therapy Evaluation Program of the NCI; and 4) the identification of new antineoplastic agents available from the Cancer Therapy Evaluation Program of the NCI; and 4) the identification of new molecular correlates of therapeutic activity and drug resistance, including new markers of DNA damage, repair, and methylation, for compounds with novel mechanisms of action, as well as for the taxane, platinum, antimetabolite, and topoisomerase I drug classes. Based on a significant record of patient accrual, as well as substantive clinical, biostatistical, and laboratory interactions during the past three years which have provided the rationale for a novel set of proposed phase I trials, the investigators at COH, USC, and UCD are well suited to rapidly complete pharmacologically-driven phase I trials of anticancer agents targeting critical new intracellular pathways.