INFUSION OF ICRF 187 FOLLOWED BY INFUSION OF TOPOTECAN IN LEUKEMIA

这项建议的目标是开发新的、以实验室为基础的化疗策略，以便在第一阶段环境中应用。这些第一阶段的研究不仅将导致分配最大耐受剂量和了解针对新的分子途径的特定抗肿瘤药物的正常组织毒性谱，而且还将提供对这些药物对关键肿瘤细胞功能的影响的机械评估。这一目标将由来自NCI指定的两个癌症中心和一家大型大学医院的一组分子药理学家和临床科学家实现，他们将利用希望之城国家医学中心(COH)小肯尼斯·诺里斯的广泛实验室和患者资源。南加州大学(USC)综合癌症中心(USC)和加州大学戴维斯癌症中心(UCD)进行第一阶段分子药效学研究，重点放在：1)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，作为一种独特的抗肿瘤活性；2)在细胞周期检查点控制或细胞周期进展中产生关键变化的新药物，作为其作用机制；3)抗肿瘤药物浓度(而不是剂量)在剂量密集化疗的疗效和毒性中的作用，以及器官功能异常对NCI癌症治疗评估计划提供的新抗肿瘤药物的药代动力学和药效学的影响；以及4)为具有新作用机制的化合物以及紫杉烷、铂、抗代谢药物和拓扑异构酶I类药物鉴定新的治疗活性和耐药性的分子相关性，包括DNA损伤、修复和甲基化的新标记物。这些试验得到以下支持：有大量的患者资源(每年超过6400名新的癌症患者)，在I期和I/II期癌症临床试验中积累了可靠的记录(1996年有350多名患者加入)，以及这三个机构之间富有成效的临床研究互动的强大历史。过去三年的实验室互动为拟议的一系列新的第一阶段试验提供了理论基础。GCRC将极大地促进COH参与这些试验，这些试验的重点是通过干细胞拯救进行输注和大剂量化疗，并包括为分子、药代动力学和药效学相关研究广泛采集样本。

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.