Purpose: To evaluate BSO-mediated glutathione (GSH) depletion in combination with L-PAM for children with recurrent or refractory high-risk neuroblastoma (NB) as a means to enhance alkylator sensitivity. Procedure: This pilot study (NCI #T95-0092) administered L-S,R-buthionine sulfoximine (BSO) as a bolus followed by 72hr continuous infusion of either 0.75g/m2/hr (level 1) or 1.0g/m2/hr (level 2) and melphalan (L-PAM) (15mg/m2 bolus at hour 48 of BSO infusion). GSH in blood mononuclear cells and bone marrow was measured by enzymatic assay, BSO in plasma by HPLC. Results: Thirty two patients received 58 courses of therapy (median 1, range 1-4 courses). Blood mononuclear cell GSH decreased (48hr) to 47%±15.7%. Level 2 mean steady-state concentration (Css) for BSO=524±207μM and peak L-PAM concentration=3.32±1.2μM. Grade 3-4 leukopenia and thrombocytopenia were common. There were two deaths from CNS toxicity and acute tubular necrosis; one had a large, intracranial mass, both were receiving cephalosporin antibiotics. No other significant toxicities were seen. There were six responses (five partial and, one mixed) representing an 18% response rate; four/six responses occurred in patients that relapsed following myeloablative therapy and included a 98% reduction in volume (cm3) of a pelvic mass, and three/five patients with >3log reduction of tumor in marrow as measured by immunocytology (sensitivity 1/105). Conclusions: BSO/L-PAM has activity against recurrent high-risk NB. Exclusion of cephalosporin antibiotics in future clinical trials of BSO may diminish the potential for serious renal and CNS toxicity.
- Reactive oxygen species