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

Clarke P. Anderson, Nino Keshelava, Noriko Satake, William H. Meek, C. Patrick Reynolds

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)659-662
Number of pages4
JournalMedical and Pediatric Oncology
Volume35
Issue number6
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Buthionine sulfoximine
  • Disease progression
  • Melphalan
  • Neuroblastoma cell lines
  • Synergism

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Oncology
  • Cancer Research

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