INTRATHECAL CAMPTOTHECIN ANALOGS FOR NEOPLASTIC MENINGITIS

原发性脑肿瘤，包括恶性胶质瘤和室管膜瘤， 仅次于白血病是儿童癌症的第二大原因。 进展 化疗和联合治疗方案，尽管取得了巨大成功 在其他儿科恶性肿瘤的治疗中，尚未被翻译 成为大多数儿童脑肿瘤的有效治疗方法。 虽然角色 化疗治疗恶性胶质瘤和室管膜瘤的效果 仍然不明确，最近的临床和实验室研究支持 经典双功能烷化剂的活性 肿瘤。 尽管如此，患者生存率大幅提高 这些药物辅助使用的结果仍有待证明，并且 了解导致药物失败的机制至关重要 用于设计最佳化疗干预措施。 成功 儿童高年级细胞系及异种移植模型的建立 神经胶质瘤和室管膜瘤现在提供了生物工具来促进 了解这些肿瘤中的烷化剂耐药性。 抵抗力 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。 对环磷酰胺的耐药机制包括 醛脱氢酶活性增加，谷胱甘肽-S-增加 转移酶活性、谷胱甘肽水平升高以及目前 髓母细胞瘤的机制尚不明确。 同样，机制 对马法兰的耐药性包括细胞运输减少、 细胞内谷胱甘肽水平保护关键细胞靶标， 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。 本提案的假设 是：儿童时期烷化剂耐药性的定义和调节/绕过 高级别神经胶质瘤和室管膜瘤将允许选择烷化剂治疗方案 积极治疗这些肿瘤并提高儿童的生存率 与这些肿瘤。 该提案的具体目标是： 1) 继续建立儿童高级别胶质瘤和室管膜瘤细胞系 以及在无胸腺小鼠中进行从头临床的可移植异种移植物， 获得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 和儿童高级神经胶质瘤和室管膜瘤细胞系的马法兰和 异种移植物包括从头移植、获得性临床移植和实验室生成的异种移植 阻力。 3) 定义对旁路/反向有效的调制 儿童高级别胶质瘤的环磷酰胺和美法仑耐药 和室管膜瘤细胞系和异种移植物，4) 定义 L- 的作用 氨基酸氧化酶介导的血浆大中性氨基酸的消耗 增强美法仑治疗中的递送和活性 皮下和颅内儿童高级别胶质瘤和室管膜瘤 无胸腺小鼠的异种移植。

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.