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.


METHODS
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.
Anderson
C P
CP
Division of Hematology-Oncology, Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.
Keshelava
N
N
Satake
N
N
Meek
W H
WH
Reynolds
C P
CP
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D019328:Buthionine Sulfoximine / Q000627:therapeutic use*; D002648:Child; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008558:Melphalan / Q000627:therapeutic use*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D019328:Buthionine Sulfoximine; D008558:Melphalan