TY - JOUR
T1 - Synergism of buthionine sulfoximine and melphalan against neuroblastoma cell lines derived after disease progression
AU - Anderson, Clarke P.
AU - Keshelava, Nino
AU - Satake, Noriko
AU - Meek, William H.
AU - Patrick Reynolds, C.
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
KW - Buthionine sulfoximine
KW - Disease progression
KW - Melphalan
KW - Neuroblastoma cell lines
KW - Synergism
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U2 - 10.1002/1096-911X(20001201)35:6<659::AID-MPO38>3.0.CO;2-4
DO - 10.1002/1096-911X(20001201)35:6<659::AID-MPO38>3.0.CO;2-4
M3 - Article
C2 - 11107141
AN - SCOPUS:0033653618
VL - 35
SP - 659
EP - 662
JO - Pediatric Blood and Cancer
JF - Pediatric Blood and Cancer
SN - 1545-5009
IS - 6
ER -