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: 6430231
• 负责人: HENRY S. FRIEDMAN
• 金额: $ 28.83万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6430231
• 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.

原发脑肿瘤，包括恶性胶质瘤和室管膜瘤， 儿童癌症的病因仅次于白血病。最新进展 化疗和联合治疗方案，尽管非常成功 在治疗其他儿科恶性肿瘤方面，还没有被翻译成 成为大多数儿童脑瘤的有效治疗方法。虽然这个角色 化疗在恶性胶质瘤和室管膜瘤治疗中的作用 仍然定义不明确，最近的临床和实验室研究支持 经典的双官能团烷基化试剂对这些化合物的活性 肿瘤。尽管如此，患者存活率的大幅提高 这些药物的辅助使用结果仍有待证实，而 了解药物失效的机制是至关重要的 用于设计最佳的化疗干预措施。成功 儿童高年级细胞系及异种移植模型的建立 胶质瘤和室管膜瘤现在提供了生物学工具来促进 了解这些肿瘤对烷化剂的耐药性。抵抗力 烷化剂，包括环磷酰胺和马法兰，是 多因素，在小鼠身上观察到了不同的机制 和人类肿瘤。对环磷酰胺耐药的机制包括 提高乙醛脱氢酶活性，增加谷胱甘肽-S- 转移酶活性，谷胱甘肽水平升高，以及目前 髓母细胞瘤的发病机制不明。与此类似的是， 对马法兰的耐药性包括细胞转运减少，增加 保护关键细胞靶标的细胞内谷胱甘肽水平， 细胞解毒和增强修复受损DNA的能力。这些 研究可能与耐药的作用机制无关 儿童恶性胶质瘤和室管膜瘤。这一提议的假设 IS：儿童期烷化剂抵抗的定义和调制/旁路 高级别胶质瘤和室管膜瘤将允许选择烷化剂方案 积极治疗这些肿瘤并提高儿童的存活率 这些肿瘤。这项建议的具体目的是：1) 继续建立儿童高级别胶质瘤和室管膜瘤细胞系 和可移植的异种移植在无症状小鼠身上， 获得性临床和实验室产生的环磷酰胺和马法兰 抵抗。2)明确环磷酰胺耐药机制 和马法兰对儿童高级别胶质瘤和室管膜瘤细胞株和 获得性临床和实验室生成的新生异种移植 抵抗。3)定义在旁路/反向中有效的调制 儿童高级别胶质瘤对环磷酰胺和马法兰的耐药性 和室管膜瘤细胞系和异种移植以及4)确定L的作用- 氨基酸氧化酶介导的血浆大分子中性氨基酸的耗竭 提高马法兰的释放量和活性 儿童高级别脑胶质瘤和室管膜瘤 裸鼠的异种移植。