Pilot study of intravenous melphalan combined with continuous infusion L-S,R -buthionine sulfoximine for children with recurrent neuroblastoma

Abstract

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.

Nifurtimox Is Effective Against Neural Tumor Cells and Is Synergistic with Buthionine Sulfoximine

“…Our determined IC50 values were similar to previously published values in similar cell lines18 and were also within the range of serum BSO levels seen in adults and children treated with BSO2146, suggesting that serum levels of BSO in our in vitro models are clinically achievable in patients with neural tumors.…”

“…BSO was also shown to be effective against neuroblastoma tumor cells, both alone and in combination with melphalan171819, and prior studies have reported that treatment of mice with human glioma and medulloblastoma xenograft tumors with BSO prior to melphalan resulted in increased survival20. Furthermore, a pilot clinical trial for treatment of children with recurrent neuroblastoma with BSO combined with melphalan demonstrated an 18% response rate21, suggesting a potential role for BSO in combination with other therapies for cancer patients.…”

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…For example, melphalan, which is detoxified by GST, showed synergistic effects with BSO in a number of tumor lines (84). Moreover, BSO and melphalan proved generally well tolerated in phase I clinical trials involving advanced cancers (85,86), the one exception being in children with recurrent neuroblastoma (87). Of note, melphalan was shown to inhibit TrxR in vitro, although this is probably not the mechanism of action at physiological plasma concentrations, as melphalan is principally an alkylating agent (88).…”

A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma

“…A previous pilot study in 32 children with neuroblastoma utilized BSO (3 g/m 2 bolus and either 0.75 or 1 g/m 2 /hr 72 hr continuous infusion) followed by melphalan (15 mg/m 2 ) without stem cell support for one to four courses. Both BSO dose levels were tolerable . GSH depletion was demonstrated in peripheral blood monocytes.…”