Melphalan Combined with Buthionine Sulfoximine

Since therapy for neuroblastoma relies heavily upon alkylating agents and acquired alkylator resistance likely contributes to recurrent disease, drugs that improve response to alkylating agents may be useful in resistant disease. Glutathione (GSH) is a ubiquitous, intracellular thiol containing tri-peptide that, along with its associated enzymes, plays a critical role in cell growth and metabolism, by maintaining the redox potential of the intracellular environment (Tew 1994; Stokes et al. 2000). Buthionine sulfoximine (BSO), a selective inhibitor of g-glutamylcysteine synthetase (g-GCS),the rate-limiting enzyme in GSH synthesis, can enhance alkylator anti-tumor efficacy in a variety of solid tumors. In vitro data have shown BSO to have significant single-agent cytotoxicity against neuroblastoma (Anderson et al. 1997,1999). Pre-treatment of neuroblastoma cell lines with only 10 pM BSO for 24 h synergistically enhanced the cytotoxicity of 10 pM melphalan by 1-2 logs of cell kill (Anderson et al. 1997). Promising results have been found in adult trials for ovarian cancer, small cell lung cancer, and melanoma, using continuous infusion of BSO and non-myeloablative doses of melphalan, with myelosuppression as the main toxicity (Bailey et al. 1997; O'Dwyer et al. 1992;Yao et al. 1993).

A pilot study of BSO (3 g/m2 bolus followed by a 72-h continuous infusion (CI) of 0.75-1.0 gm/m2 h-1) and L-PAM (15 mg/m2 bolus at hour 48 of BSO infusion) was carried out in 32 patients with recurrent neuroblastoma (Anderson et al. 1998). Of 31 evalu-

able patients, there were 7 partial responses (PR), 2 minor responses (MR), 9 stable disease (SD), and 13 patients with progressive disease (PD). Nearly all patients experienced grade-3 leukopenia and thrombocytopenia, plus grade-2 nausea. There were two toxic deaths on study secondary to renal and CNS toxicity. At autopsy, both children had evidence of mid-brain edema and eosinophilic necrosis of the pons. Other patients on study showed no consistent pattern of impending renal/neurologic toxicity (Anderson et al. 1998). A phase-I study of BSO with melphalan is underway in the New Approaches to Neuroblastoma Therapy (NANT) consortium (N9902), which increases the melphalan to myeloablative doses with peripheral blood stem-cell support,while holding the BSO infusion constant, with close monitoring for possible renal or neurologic toxicity.

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