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令人沮丧的肿瘤 需要治疗的肿瘤，很大程度上是由于这些病变产生和生长的敏感部位。化疗在恶性神经胶质瘤和髓母细胞瘤治疗中的作用不断发展。氯乙基亚硝基脲 (CENU) 最初被选择用于治疗中枢神经系统肿瘤，因为其具有良好的理化特性，例如亲脂性以及对小鼠颅内生长的 L1210 白血病细胞的活性。然而，尽管恶性神经胶质瘤对 BCNU 或 CCNU 具有中等敏感性，但 CENU 仅略微改变了恶性脑肿瘤患者的生存率。 CENU（例如 BCNU）在水解后产生高反应性 2-氯乙基碳鎓离子，可通过乙烯桥双功能烷基化和交联 DNA、RNA 和蛋白质。抗肿瘤 CENU 的活性似乎与 DNA 链间交联 (ICL) 的形成成正比。 对烷化剂（包括 CENU）的耐药性是多因素的，在小鼠和人类肿瘤中观察到多种机制。这些机制包括通过 O6-烷基鸟嘌呤-DNA 烷基转移酶去除最初的 CENU 诱导的单加合物或通过谷胱甘肽猝灭单加合物。 然而，CENU 诱导的 DNA ICL 不易受到 AGT 去除或谷胱甘肽猝灭的影响。因此，形成 DNA ICL 的肿瘤细胞对 CENU 的抵抗必定是由于 AGT 或谷胱甘肽-肿瘤细胞相互作用以外的替代机制所致。该提案的假设是：DNA ICL修复是恶性胶质瘤和髓母细胞瘤对氯乙基亚硝基脲耐药的主要机制。该提案的具体目标是： 1. 定义介导人类细胞提取物修复 BCNU 诱导的 DNA ICL 的分子事件； 2. 定义可用于去除 BCNU 诱导的 DNA ICL 的 DNA 修复途径； 3. 明确 BCNU 诱导的 DNA ICL 修复在介导耐药性中的作用。