Synergism of buthionine sulfoximine and melphalan against neuroblastoma cell lines derived after disease progression

Background. Despite intensive-alkylator based regimens, >50% of patients with high-risk neuroblastoma (NB) die from recurrent disease that is probably due, in part, to acquired alkylator resistance. Procedure. Using buthionine sulfoximine (BSO)-mediated, glutathione (GSH) depletion to modulate melphalan (L-PAM) resistance, we examined six NB cell lines established after progressive disease following either standard chemotherapy, BSO/L-PAM therapy, or myeloablative therapy and autologous hematopoietic stem cell transplant (AHSCT). Results. Four of the six cell lines (three p53-nonfunctional and one p53-functional) showed high-level L-PAM resistance. Conclusions. Fixed ratio analysis demonstrated BSO/L-PAM synergy (combination index >1) for all cell lines tested, in L-PAM-resistant cell lines, the minimal cytotoxicity observed for BSO combined with nonmyeloablative concentrations of L-PAM was markedly enhanced (>4 logs total cell kill) when BSO was combined with myeloablative concentrations of L-PAM. In alkylator-resistant NB, the optimal use of BSO may require dose escalation of L-PAM to levels requiring AHSCT. (C) 2000 Wiley-Liss, Inc.