PILOT OF BUTHIONINE SULFOXIMINE WITH MELPHALAN IN NEUROBLASTOMA

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，但获得性耐药可能起主要作用。本研究将评估丁硫素亚砜胺（bso）与美伐兰联合应用于小儿神经母细胞瘤患者的药代动力学和临床毒性。临床前研究表明谷胱甘肽通过对烷基化损伤的解毒作用在化疗耐药中起作用，而BSO作为谷胱甘肽合成的选择性抑制剂，可以恢复烷基化剂的敏感性。本研究的另一个目标是记录外周血淋巴细胞，正常骨髓和骨髓中发现的神经母细胞瘤细胞中的谷胱甘肽（GSH）耗竭。

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.