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

Background. Despite intensive-alkylator based regimens, > 50% of patients w ith highrisk neuroblastoma (NB) die from recurrent disease that is probably due, in part, to acquired alkylator resistance. Procedure. Using buthionin e sulfoximine (BSO)-mediated, glutathione (GSH) depletion to modulate melph alan (L-PAM) resistance, we examined six NE cell lines established after pr ogressive disease following either standard chemotherapy, BSO/L-PAM therapy , or myeloablative therapy and autologous hematopoietic stem cell transplan t (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 a ll cell lines tested. In L-PAM-resistant cell lines, the minimal cytotoxici ty 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 optim al use of BSO may require dose escalation of L-PAM to levels requiring AHSC T. Med. Pediatr. Oncol. 35:659-662, 2000. (C) 2000 Wiley-Liss, Inc.