ALKYLATOR RESISTANCE IN CHILDHOOD GLIOMA AND EPENDYMOMA

儿童神经胶质瘤和室管膜瘤中的烷基化剂耐药性

• 批准号: 6243547
• 负责人: HENRY S. FRIEDMAN
• 金额: $ 19.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243547
• 关键词: aldehyde dehydrogenases; alkylating agents; aminoacid oxidase; antineoplastics; athymic mouse; buthionine sulfoximine; cyclophosphamide; disease /disorder model; drug interactions; drug resistance; ependymoma; fasting; glioma; glutathione transferase; human tissue; melphalan; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; neoplastic cell; pediatric neoplasm /cancer; pediatric pharmacology; pharmacokinetics; tissue /cell culture; xenotransplantation

Primary brain tumors, including malignant gliomas and ependymomas, are second only to leukemia as a cause of childhood cancer. Advances in chemotherapy and combined modality regimens, though dramatically successful in the treatment of other pediatric malignancies, have not been translated into effective therapy for most pediatric brain tumors. Although the role of chemotherapy in the treatment of malignant gliomas and ependymomas remains poorly defined, recent clinical and laboratory studies support the activity of the classical bifunctional alkylating agents against these tumors. Nevertheless, substantial increases in patient survival as a result of adjuvant use of these agents remain to be demonstrated, and an understanding of the mechanisms responsible for drug failure is critical for the design of optimal chemotherapeutic intervention. Successful establishment of cell line and xenograft models of childhood high grade glioma and ependymoma now provide the biological tools to facilitate an understanding of alkylator resistance in these tumors. Resistance to alkylating agents, including cyclophosphamide and melphalan, is multifactorial, with a diverse spectrum of mechanisms observed in murine and human neoplasia. Mechanisms of resistance to cyclophosphamide include increased aldehyde dehydrogenase activity., increased glutathione-S- transferase activity, elevated levels of glutathione, and a presently undefined mechanism in medulloblastoma. Similarly, mechanisms of resistance to malphalan include decreased cellular transport, increased intracellular glutathione levels protective of critical cellular targets, cellular detoxification and enhanced capacity to repair damaged DNA. These studies may not be relevant to the mechanisms of resistance operational in childhood malignant glioma and ependymoma. The hypothesis of this proposal is: definition and modulation/bypass of alkylator resistance in childhood high grade glioma and ependymoma will allow selection of alkylator regimens active in the treatment of these tumors and increase survival of children with these neoplasms. The specific aims of this proposal are: 1) To continue to establish childhood high grade glioma and ependymoma cell lines and transplantable xenografts in athymic mice with de novo clinical, acquired clinical and laboratory-generated cyclophosphamide and melphalan resistance. 2) To define the mechanisms of resistance to cyclophosphamide and melphalan of childhood high grade glioma and ependymoma cell lines and xenografts with de novo, acquired clinical, and laboratory-generated resistance. 3) To define modulation effective in bypassing/reversing cyclophosphamide and melphalan resistance in childhood high grade glioma and ependymoma cell lines and xenografts and 4) To define the role of L- amino acid oxidase-mediated depletion of plasma large neutral amino acids to enhance delivery and activity of melphalan in the treatment of subcutaneous and intracranial childhood high grade glioma and ependymoma xenografts in athymic mice.

原发性脑肿瘤，包括恶性神经胶质瘤和膜膜瘤，是 仅次于白血病是儿童癌症的原因。 进步 化学疗法和组合方式方案，尽管取得了巨大成功 在治疗其他儿科恶性肿瘤中，尚未翻译 进入大多数小儿脑肿瘤的有效疗法。 虽然角色 化学疗法治疗恶性神经胶质瘤和性膜瘤 仍然定义不明，最近的临床和实验室研究支持 经典双功能烷基化剂对这些的活性 肿瘤。 然而，作为一个患者生存的大幅增加 辅助使用这些药物的结果仍有待证明，并且 了解导致药物衰竭的机制至关重要 用于设计最佳化学治疗干预措施。 成功的 建立细胞系和异种移植童年高级模型 神经胶质瘤和室心瘤现在提供了生物学工具，以促进 对这些肿瘤中烷基抗性的了解。 抵抗 烷基化剂，包括环磷酰胺和Melphalan，是 多因素，在鼠中观察到各种机制 和人类肿瘤。 对环磷酰胺的抗性机制包括 增加醛脱氢酶活性增加，谷胱甘肽-S-增加 转移酶活性，谷胱甘肽水平升高，目前为 髓母细胞瘤中未定义的机制。 同样，机制 对Malphalan的耐药性包括细胞运输减少，增加 细胞内谷胱甘肽水平保护关键细胞靶标， 细胞排毒和修复受损DNA的能力增强。 这些 研究可能与抗药性机制无关 儿童期恶性神经胶质瘤和感染性。 该提议的假设 IS：儿童时期烷基抗性的定义和调制/旁路 高级神经胶质瘤和室心瘤将允许选择烷基动物方案 积极治疗这些肿瘤并增加儿童的存活率 使用这些肿瘤。 该提议的具体目的是：1） 继续建立儿童期高级神经胶质瘤和感染细胞系 并在Noko Clinical的无性小鼠中移植异种移植物， 获得的临床和实验室生成的环磷酰胺和Melphalan 反抗。 2）定义对环磷酰胺的抗性机制 和儿童期高级神经胶质瘤和感染细胞系的Melphalan以及 带有从头，获得的临床和实验室生成的异种移植物 反抗。 3）定义有效绕过/反向的调制 儿童期高级神经胶质瘤中的环磷酰胺和梅尔法兰抗性 和室心瘤细胞系和异种移植物以及4）定义L-的作用 血浆大中性氨基酸的氨基酸氧化酶介导的耗竭 增强Melphalan在治疗中的交付和活动 皮下和颅内儿童期高级神经胶质瘤和膜瘤 无胸腺小鼠的异种移植物。