PILOT OF BUTHIONINE SULFOXIMINE WITH MELPHALAN IN NEUROBLASTOMA

丁硫氨酸亚磺酰亚胺联合美法仑治疗神经母细胞瘤的试验

• 批准号: 6303706
• 负责人: CLARK ANDERSON
• 金额: $ 3.56万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6303706
• 关键词: buthionine sulfoximine; child (0-11); clinical research; drug screening /evaluation; glutathione; human subject; lymphocyte; melphalan; neoplasm /cancer chemotherapy; neuroblastoma; pediatric neoplasm /cancer; pediatric pharmacology; pharmacokinetics

Neuroblastoma, which arises from the sympathetic nervous system, is the most common extracranial solid tumor of childhood. One of the challenges faced in the treatment of neuroblastoma is that while many children with metastatic disease initially respond to therapy, the tumor recurs and the child dies from progressive disease. The causes for treatment failure are mutifactorial, but acquired drug resistance probably plays a major role. This study will evaluate the pharmacokinetics and clinical toxicities of the combination of buthionin sulfoximine (BS0) and melphalan in pediatric patients with neuroblastoma. Pre-clinical studies have shown that glutathione plays a role in chemotherapy resistance by detoxification of alkylator damage and that BSO, a selectidve inhibitor of glutathione synethesis, can restore sensitivity of alkylating agents. An additional goal of this study is to document glutathione (GSH) depletion in peripheral blood lymphocytes, normal marrow and neuroblastoma cells found in the bone marrow.

神经母细胞瘤起源于交感神经系统，是儿童最常见的颅外实体瘤。神经母细胞瘤治疗面临的挑战之一是，虽然许多患有转移性疾病的儿童最初对治疗有反应，但肿瘤复发，儿童死于进展性疾病。治疗失败的原因是多方面的，但获得性耐药性可能是主要原因。本研究将评价丁硫辛亚磺胺(BS0)联合马法兰治疗儿童神经母细胞瘤的药代动力学和临床毒性。临床前研究表明，谷胱甘肽通过解毒烷基化损伤而在化疗耐药中发挥作用，而谷胱甘肽合成的选择性抑制剂BSO可以恢复烷基化药物的敏感性。这项研究的另一个目标是证明在外周血淋巴细胞、正常骨髓和骨髓中发现的神经母细胞瘤细胞中谷胱甘肽(GSH)的耗竭。