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 language | English (US) |
|---|---|
| Pages (from-to) | 659-662 |
| Number of pages | 4 |
| Journal | Medical and Pediatric Oncology |
| Volume | 35 |
| Issue number | 6 |
| DOIs | |
| State | Published - 2000 |
| Externally published | Yes |
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Keywords
- Buthionine sulfoximine
- Disease progression
- Melphalan
- Neuroblastoma cell lines
- Synergism
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Oncology
- Cancer Research
Cite this
Synergism of buthionine sulfoximine and melphalan against neuroblastoma cell lines derived after disease progression. / Anderson, Clarke P.; Keshelava, Nino; Satake, Noriko; Meek, William H.; Patrick Reynolds, C.
In: Medical and Pediatric Oncology, Vol. 35, No. 6, 2000, p. 659-662.Research output: Contribution to journal › Article
}
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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UR - http://www.scopus.com/inward/citedby.url?scp=0033653618&partnerID=8YFLogxK
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
VL - 35
SP - 659
EP - 662
JO - Pediatric Blood and Cancer
JF - Pediatric Blood and Cancer
SN - 1545-5009
IS - 6
ER -