CLINICAL APPLICATIONS OF MODULATION OF DNA REPAIR PATHWAYS

本特定目标中概述的临床研究针对的是操作 06-甲基鸟嘌呤DNA甲基转移酶（MGMT）在人类中的作用， 广泛的临床前工作的结果证明了 动物模型的方法。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（CENUs）。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 美国印第安纳州大学国家基因载体实验室 审判该临床研究建立在目前印第安纳州的一项试点研究基础上 大学，由Regina Jakacki博士设计，部分由NCI支持 资金，其中利用外周血干祖细胞输注 以减少造血毒性并允许时间表压缩 广泛使用的称为“PCV”的脑治疗方案（甲基苄肼， CCNU，长春新碱）。 第二个项目旨在减少肿瘤中MGMT的表达 细胞根据伦纳德埃里克森博士的临床前工作，MGMT可以 通过连续治疗有效地从肿瘤细胞系中消除 与产生MGMT的天然底物，06-甲基鸟嘌呤， 或直接作为MGMT的底物。一种这样的药剂，06-苄基鸟嘌呤 （6-BG），目前正在其他机构进行I期试验。具体 本研究的目的是：1）进行剂量强化的初步研究， 丙卡巴肼、环己亚硝脲、长春新碱（PCV）用于预后不良的儿童， 利用纤连蛋白辅助的逆转录病毒介导的成人脑肿瘤 用06-甲基鸟嘌呤DNA修饰CD 34+外周血细胞 甲基转移酶（MGMT）。2)进行第一阶段试验， 06-苄基鸟嘌呤和BCNU的组合的毒性，并检查 在用以下药物治疗的患者的肿瘤活检中MGMT活性的抑制 这种联合化疗用于复发性B细胞恶性肿瘤。

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.