INTRATHECAL CAMPTOTHECIN ANALOGS FOR NEOPLASTIC MENINGITIS

鞘内注射喜树碱类似物治疗肿瘤性脑膜炎

• 批准号: 6593427
• 负责人: HENRY S. FRIEDMAN
• 金额: $ 31.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6593427
• 关键词: analog; antineoplastics; athymic mouse; camptothecin; disease /disorder model; drug administration routes; drug adverse effect; drug resistance; drug screening /evaluation; glioma; human tissue; infection related neoplasm /cancer; medulloblastoma; meningitis; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; pharmacokinetics; subarachnoid space; topotecan; 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室管膜瘤， 是仅次于白血病的第二大儿童癌症病因。 进展 化疗和综合治疗方案，尽管取得了巨大成功 在其他儿科恶性肿瘤的治疗中，尚未翻译 有效治疗小儿脑肿瘤 虽然角色 恶性胶质瘤和室管膜瘤的化疗 仍然定义不清，最近的临床和实验室研究支持 经典的双官能烷基化剂对这些化合物的活性 肿瘤的 尽管如此，作为一种治疗方法， 辅助使用这些药物的结果仍有待证实， 了解药物失效的机制是至关重要的 来设计最佳的化疗干预。 成功 儿童高分化骨髓瘤细胞系及异种移植模型建立 神经胶质瘤和室管膜瘤现在提供了生物学工具， 了解这些肿瘤中的烷化剂耐药性。 抗 烷化剂，包括环磷酰胺和美法仑， 多因素，在小鼠中观察到多种机制 和人类肿瘤。 环磷酰胺耐药机制包括 醛脱氢酶活性增加，谷胱甘肽-S- 转移酶活性，谷胱甘肽水平升高，目前 髓母细胞瘤的机制尚未明确。 同样， 对马法兰的抗性包括细胞转运减少， 细胞内谷胱甘肽水平保护关键的细胞靶点， 细胞解毒和增强修复受损DNA的能力。 这些 研究可能与耐药机制无关， 儿童恶性胶质瘤和室管膜瘤。 这个提议的假设 是：定义和调制/旁路的烷化剂耐药性在儿童 高级别胶质瘤和室管膜瘤将允许选择烷化剂方案 积极治疗这些肿瘤，提高儿童的生存率 这些肿瘤。 这项建议的具体目标是：1） 继续建立儿童高级别胶质瘤和室管膜瘤细胞系 和无胸腺小鼠中的可移植异种移植物， 获得性临床和实验室产生的环磷酰胺和美法仑 阻力 2)明确环磷酰胺耐药机制 和美法仑对儿童高级别胶质瘤和室管膜瘤细胞系的作用， 具有新发、获得性临床和实验室生成的异种移植物 阻力 3)定义旁路/反向中有效的调制 儿童高级别胶质瘤对环磷酰胺和美法仑耐药 和室管膜瘤细胞系和异种移植物，以及4）为了确定L- 氨基酸氧化酶介导的血浆大分子中性氨基酸耗竭 以增强美法仑在治疗 儿童皮下和颅内高级别胶质瘤和室管膜瘤 无胸腺小鼠中的异种移植物。