CLINICAL APPLICATIONS OF MODULATION OF DNA REPAIR PATHWAYS

在这一特定目标中概述的临床研究针对的是手法 人类中的06-甲基鸟嘌呤DNA甲基转移酶(MGMT)，是 广泛的临床前工作结果证明了该方法的有效性 动物模型中的方法。其中一个项目提议增加 MGMT在造血细胞中的表达 累积性骨髓抑制常见于 氯乙基亚硝脲(Cenus)这个项目利用了一种重组 逆转录病毒载体在小鼠研究中进行了广泛的测试，并由 印第安纳大学人类临床国家基因载体实验室 审判。这项临床研究建立在印第安纳州目前的一项先导研究的基础上 大学，由Regina Jakacki博士设计，部分由NCI支持 资金，用于外周血干/祖细胞输注 减少造血毒性并允许计划压缩 被广泛使用的称为“PCV”的脑部治疗方案(procarbazine， CCNU，长春新碱)。 第二个项目旨在减少MGMT在肿瘤中的表达 细胞。根据伦纳德·埃里克森博士的临床前工作，MGMT可以 通过序贯治疗有效地耗尽了肿瘤细胞系 使用产生MGMT，06-甲基鸟嘌呤的天然底物的试剂， 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第一阶段试验。具体的 这项研究的目的是：1)进行剂量强化的初步研究 丙卡巴肼、环胞嘧啶、长春新碱(PCV)治疗儿童和老年人预后不良 利用纤维连接蛋白辅助、逆转录病毒介导的成人脑瘤 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-苄基鸟嘌呤与BCNU的联合毒性及检测 抗肿瘤药物治疗对肿瘤活检组织中MGMT活性的抑制作用 这种联合化疗治疗复发的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.