INFUSION OF ICRF 187 FOLLOWED BY INFUSION OF TOPOTECAN IN LEUKEMIA

本提案的目的是开发新的、基于实验室的化疗治疗策略，以应用于I期环境。这些I期研究不仅将导致最大耐受剂量的分配，并了解针对新分子途径的特定抗肿瘤药物的正常组织毒性谱，而且还将提供药物对关键肿瘤细胞功能影响的机制评估。这一目标将由来自两个nci指定的癌症中心和一个大型大学医院的一组分子药理学家和临床科学家来实现，他们将利用希望之城国家医疗中心（COH）、南加州大学（USC）的小肯尼斯·诺里斯综合癌症中心和加州大学的广泛实验室和患者资源。戴维斯癌症中心（UCD）进行I期分子药效学研究，重点是：1)作为一种独特的抗肿瘤活性，能够显著改变DNA甲基化模式或直接抑制DNA甲基转移酶活性的新化合物；2)在细胞周期检查点控制或细胞周期进程中产生关键改变的新药物作为其作用机制；3)抗肿瘤药物浓度（而不是剂量）在剂量强化化疗的疗效和毒性中的作用，以及器官功能异常对NCI癌症治疗评估项目提供的新型抗肿瘤药物的药代动力学和药效学的影响；4)鉴定治疗活性和耐药性的新分子相关物，包括DNA损伤、修复和甲基化的新标记物，以及具有新作用机制的化合物，以及紫杉烷类、铂类、抗代谢物类和拓扑异构酶类药物。这些试验得到了大量患者资源的支持（每年超过6400名新癌症患者），I期和I/II期癌症临床试验累积的良好记录（1996年超过350名患者加入），以及三个机构之间富有成效的临床研究互动的强大历史。在过去的三年里，实验室的相互作用为一组新的拟议的I期试验提供了基本原理。GCRC将极大地促进COH参与试验，这些试验侧重于输注和高剂量化疗与干细胞拯救，并包括广泛的样品采集用于分子，药代动力学和药效学相关研究。

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 (UCD) 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 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. These trials are supported by the availability of a large patient resource (in excess of 6,400 new cancer patients per year), a proven track record of accrual to Phase I and I/II cancer clinical trials (over 350 patient accessions in 1996), and a strong history of productive clinical research interactions among the three institutions. Laboratory interactions during the past three years have provided the rationale for a novel set of proposed Phase I trials. The GCRC will greatly facilitate participation by the COH in the trials, which focus on infusional and high-dose chemotherapy with stem-cell rescue, and which include extensive sample acquisition for molecular, pharmacokinetic and pharmacodynamic correlative studies.