DNA Repair-Mediated BCNU Resistance in CNS Tumors

CNS 肿瘤中 DNA 修复介导的 BCNU 耐药性

• 批准号: 6963064
• 负责人: HENRY S. FRIEDMAN
• 金额: $ 24.11万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6963064
• 关键词: analog; antineoplastics; athymic mouse; camptothecin; central nervous system neoplasms; disease /disorder model; drug administration routes; drug adverse effect; drug resistance; drug screening /evaluation; glioma; human tissue; infection related neoplasm /cancer; lomustine; medulloblastoma; meningitis; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; pharmacokinetics; subarachnoid space; topotecan; xenotransplantation

Malignant central nervous system (CNS) tumors are perhaps the most difficult and frustrating neoplasms to treat, in large part due to the sensitive site in which these lesions arise and grow. The role of chemotherapy in the treatment of both malignant glioma and medulloblastoma continues to evolve. The chloroethylnitrosoureas (CENUs) were originally chosen for treatment of central nervous system tumors on the basis of favorable physiochemical properties such as lipophilicity as well as activity against L1210 leukemia cells growing intracranially in mice. Nevertheless, despite moderate sensitivity of malignant glioma to BCNU or CCNU, the CENUs have only modestly altered survival for patients with malignant brain tumors. CENUs such as BCNU produce highly reactive 2-chloroethyl carbonium ions following hydrolysis which can bifunctionally alkylate and crosslink DNA, RNA and proteins via ethylene bridges. The antitumor activity of CENUs appears to be proportional to DNA interstrand crosslink (ICL) formation. Resistance to alkylating agents including CENUs is multifactorial, with a diverse spectrum of mechanisms observed in murine and human neoplasia. These mechanisms include removal of the initial CENUs-induced mono-adduct by O6-alkylguanine-DNA alkyltransferase or quenching of the mono-adduct by glutathione. However, CENU-induced DNA ICL are not susceptible to either AGT removal or glutathione quenching. Therefore, resistance to CENUs in tumor cells in which DNA ICL are formed must be due to alternative mechanisms other than AGT-or glutathione-tumor cell interactions. The hypothesis of this proposal is that: repair of DNA ICL is a major mechanism of resistance to chloroethylnitrosoureas in malignant glioma and medulloblastoma. The specific aims of this proposal are: 1. Define molecular events mediating repair of BCNU-induced DNA ICL by human cell extracts; 2. Define the DNA repair pathways operational in removal of BCNU-induced DNA ICL; and 3. Define the role of repair of BCNU-induced DNA ICL in mediating resistance.

恶性中枢神经系统（CNS）肿瘤可能是最困难和最令人沮丧的 在很大程度上是由于这些病变出现并生长的敏感部位，因此在很大程度上可以治疗肿瘤。化学疗法在治疗恶性神经胶质瘤和髓母细胞瘤的作用继续发展。最初根据有利的生理化学特性（例如亲脂性和针对L1210白血病细胞在小鼠内生长的L1210白血病细胞）选择氯乙基硝酸（CENUS）来治疗中枢神经系统肿瘤。然而，尽管恶性神经胶质瘤对BCNU或CCNU的敏感性适度，但Cenus对于恶性脑肿瘤患者的存活率仅适度改变。水解后Cenus（例如BCNU）在水解后产生高反应性的2-氯乙基碳离子，可以通过乙烯桥从烷基化和交叉链接DNA，RNA和蛋白质上分开。抗肿瘤 Cenus的活性似乎与DNA链间交联（ICL）形成成正比。 包括Cenus在内的烷基化剂的耐药性是多因素的，在鼠和人类肿瘤中观察到各种机制。这些机制包括去除O6-烷基鸟嘌呤-DNA烷基转移酶的初始Cenus诱导的单一添加或通过谷胱甘肽对单一添加的淬灭。 但是，CENU诱导的DNA ICL不容易被AGT去除或谷胱甘肽淬火。因此，形成DNA ICL的肿瘤细胞中对Cenus的耐药性必须是由于Agt-or Glutathione-Tumor细胞相互作用以外的其他机制。该提议的假设是：DNA ICL的修复是恶性神经胶质瘤和髓母细胞瘤中对氯乙基硝基库的抗性的主要机制。该提案的具体目的是：1。定义分子事件，介导人类细胞提取物对BCNU诱导的DNA ICL的修复； 2。定义DNA修复途径在去除BCNU诱导的DNA ICL时运行；和3。定义了BCNU诱导的DNA ICL修复在介导抗性中的作用。