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. Copyright 2000 Wiley-Liss, Inc.
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. Copyright 2000 Wiley-Liss, Inc.
Authors: Mario Faundez; Laura Pino; Paula Letelier; Carla Ortiz; Rodrigo López; Claudia Seguel; Jorge Ferreira; Mario Pavani; Antonio Morello; Juan Diego Maya Journal: Antimicrob Agents Chemother Date: 2005-01 Impact factor: 5.191
Authors: Kyu Kwang Kim; Rakesh K Singh; Robert M Strongin; Richard G Moore; Laurent Brard; Thilo S Lange Journal: PLoS One Date: 2011-04-29 Impact factor: 3.240