CLINICAL APPLICATIONS OF MODULATION OF DNA REPAIR PATHWAYS

DNA 修复途径调节的临床应用

• 批准号: 6300582
• 负责人: KENNETH CORNETTA
• 金额: $ 24.8万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-06 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300582
• 关键词: CD34 molecule; DNA repair; antineoplastics; biopsy; brain neoplasms; carmustine; clinical research; clinical trial phase I; combination cancer therapy; cytotoxicity; drug screening /evaluation; enzyme activity; enzyme inhibitors; genetic manipulation; human subject; human therapy evaluation; lomustine; methyltransferase; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplastic cell; pharmacokinetics; procarbazine; streptozotocin; vincristine

The clinical studies outlined in this specific aim target the manipulation of 06-methylguanine DNA methyltransferase (MGMT) in humans and are the result of extensive pre-clinical work demonstrating the efficacy of the approaches in animal models. One project proposes to increase the expression of MGMT in hematopoietic cells in an effort to diminish the cumulative myelosuppression commonly encountered with chloroethylnitrosoureas (CENUs). This project utilizes a recombinant retroviral vector extensively tested in murine studies and produced by the National Gene Vector Laboratory at Indiana University for human clinical trials. The clinical study builds on a current pilot study at Indiana University, designed by Dr. Regina Jakacki and supported in part by NCI funding, which utilities peripheral blood stem-progenitor cell infusions to decrease hematopoietic toxicities and allow schedule compression of an extensively used brain treatment protocol called "PCV" (procarbazine, CCNU, vincristine). The second project is designed to diminish expression of MGMT in tumor cells. Based on pre-clinical work by Dr. Leonard Erickson, MGMT can be effectively depleted from tumor cell lines by the sequential treatment with agents that produce the natural substrate for MGMT, 06-methylguanine, or act as a substrate for MGMT directly. One such agent, 06-benzylguanine (6-BG), is currently in phase I trials at other institutions. The specific aims of the study are: 1) To conduct a pilot study of dose-intensified procarbazine, CCNU, vincristine (PCV) for poor prognosis pediatric and adult brain tumor utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with 06-methylguanine DNA methyltransferase (MGMT). 2) To conduct a phase I trial to determine the toxicity of the combination of 06-benzylguanine and BCNU, and to examine the inhibition of MGMT activity in tumor biopsies in patients treated with this combination chemotherapy for relapsed B cell malignancies.

该具体目标中概述的临床研究针对的是操纵 人类中 06-甲基鸟嘌呤 DNA 甲基转移酶 (MGMT) 的 大量临床前工作的结果证明了该药物的功效 动物模型中的方法。一个项目建议增加 MGMT 在造血细胞中的表达，以减少 累积性骨髓抑制常见于 氯乙基亚硝基脲 (CENU)。该项目利用重组 逆转录病毒载体在小鼠研究中进行了广泛测试，并由 印第安纳大学国家基因载体实验室用于人类临床 试验。该临床研究建立在印第安纳州目前的一项试点研究的基础上 大学由 Regina Jakacki 博士设计并由 NCI 部分支持 资金，用于外周血干祖细胞输注 减少造血毒性并允许日程压缩 广泛使用的脑部治疗方案称为“PCV”（丙卡巴嗪， CCNU，长春新碱）。 第二个项目旨在减少肿瘤中 MGMT 的表达 细胞。根据 Leonard Erickson 博士的临床前工作，MGMT 可以 通过序贯治疗有效地消除肿瘤细胞系 使用产生 MGMT 天然底物 06-甲基鸟嘌呤的试剂， 或直接作为 MGMT 的底物。一种这样的试剂，06-苄基鸟嘌呤 (6-BG)，目前正在其他机构进行 I 期试验。具体的 该研究的目的是： 1) 进行剂量强化的初步研究 丙卡巴肼、CCNU、长春新碱 (PCV) 用于治疗预后不良的儿科和 利用纤连蛋白辅助、逆转录病毒介导的成人脑肿瘤 用 06-甲基鸟嘌呤 DNA 修饰 CD34+ 外周血细胞 甲基转移酶（MGMT）。 2) 进行第一阶段试验以确定 06-苄基鸟嘌呤和BCNU的组合的毒性，并检查 治疗患者肿瘤活检中 MGMT 活性的抑制 这种联合化疗用于治疗复发的 B 细胞恶性肿瘤。