Synergistic cytotoxicity of buthionine sulfoximine (BSO) and intensive melphalan (L-PAM) for neuroblastoma cell lines established at relapse after myeloablative therapy

被引:44
作者
Anderson, CP
Reynolds, CP
机构
[1] Childrens Hosp, Div Hematol Oncol, Los Angeles, CA 90027 USA
[2] Univ So Calif, Keck Sch Med, Dept Pediat, Los Angeles, CA 90089 USA
[3] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90089 USA
关键词
buthionine sulfoximine; melphalan; alkylator resistance; glutathione; neuroblastoma;
D O I
10.1038/sj.bmt.1703605
中图分类号
Q6 [生物物理学];
学科分类号
071011 ;
摘要
Patients with high-risk neuroblastoma (NB) initially respond to aggressive, alkylator-based therapy only to die from recurrent disease that is refractory to chemotherapy, including alkylating agents. We examined the ability of buthionine sulfoximine (BSO)-mediated glutathione (GSH) depletion to modulate melphalan (LPAM) resistance in five NB cell lines established after progressive disease following myeloablative therapy (high-dose melphalan, carboplatin, etoposide and total body irradiation) supported by autologous hematopoietic stem cell transplant (AHSCT), and in 15 NB cell lines established at diagnosis or after non-myeloablative therapy (pre-AHSCT). Four of five post-AHSCT NB cell lines and 10 of 15 pre-AHSCT NB cell lines were sensitive to single agent BSO (LC90 <300 mum BSO), while two of five post-AHSCT lines and one of 15 pre-AHSCT lines showed high-level resistance to L-PAM (LC90 >30 mum). Fixed ratio analysis demonstrated BSO/L-PAM synergy (combination index <1) for all five post-AHSCT and for all 15 pre-AHSCT cell lines tested. Multi-log cytotoxicity (often exceeding four logs of cell kill) was observed in post-AHSCT L-PAM-resistant cell lines (including p53 non-functional lines) only when clinically achievable concentrations of BSO were combined with myeloablative concentrations of L-PAM. We conclude that most neuroblastoma cell lines, including post-AHSCT NB cell lines that are highly resistant to myeloablative levels of L-PAM and lack p53 function, are sensitive to clinically achievable concentrations of L-PAM and BSO. However, some L-PAM-resistant NB cell lines (especially those lacking p53 function) require dose escalation of L-PAM to myeloablative concentrations in order to demonstrate significant synergistic cytotoxicity. Thus, optimal clinical application of BSO/L-PAM may require AHSCT.
引用
收藏
页码:135 / 140
页数:6
相关论文
共 42 条
[1]   Buthionine sulphoximine alone and in combination with melphalan (L-PAM) is highly cytotoxic for human neuroblastoma cell lines [J].
Anderson, CP ;
Tsai, J ;
Chan, W ;
Park, CK ;
Tian, L ;
Lui, RM ;
Forman, HJ ;
Reynolds, CP .
EUROPEAN JOURNAL OF CANCER, 1997, 33 (12) :2016-2019
[2]   Buthionine sulfoximine and myeloablative concentrations of melphalan overcome resistance in a melphalan-resistant neuroblastoma cell line [J].
Anderson, CP ;
Seeger, RC ;
Satake, N ;
Monforte-Munoz, HL ;
Keshelava, N ;
Bailey, HH ;
Reynolds, CP .
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, 2001, 23 (08) :500-505
[3]   Depletion of glutathione by buthionine sulfoximine is cytotoxic for human neuroblastoma cell lines via apoptosis [J].
Anderson, CP ;
Tsai, JM ;
Meek, WE ;
Liu, RM ;
Tang, YM ;
Forman, HJ ;
Reynolds, CP .
EXPERIMENTAL CELL RESEARCH, 1999, 246 (01) :183-192
[4]  
Anderson CP, 1999, MED PEDIATR ONCOL, V33, P158
[5]  
ANDERSON CP, 1998, P AN M AM SOC CLIN, V17, pA531
[6]   PHASE-I CLINICAL-TRIAL OF INTRAVENOUS L-BUTHIONINE SULFOXIMINE AND MELPHALAN - AN ATTEMPT AT MODULATION OF GLUTATHIONE [J].
BAILEY, HH ;
MULCAHY, RT ;
TUTSCH, KD ;
ARZOOMANIAN, RZ ;
ALBERTI, D ;
TOMBES, MB ;
WILDING, G ;
POMPLUN, M ;
SPRIGGS, DR .
JOURNAL OF CLINICAL ONCOLOGY, 1994, 12 (01) :194-205
[7]   Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan [J].
Bailey, HH ;
Ripple, G ;
Tutsch, KD ;
Arzoomanian, RZ ;
Alberti, D ;
Feierabend, C ;
Mahvi, D ;
Schink, J ;
Pomplun, M ;
Mulcahy, RT ;
Wilding, G .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1997, 89 (23) :1789-1796
[8]   THE ROLE OF THIOLS IN CELLULAR-RESPONSE TO RADIATION AND DRUGS [J].
BIAGLOW, JE ;
VARNES, ME ;
CLARK, EP ;
EPP, ER .
RADIATION RESEARCH, 1983, 95 (03) :437-455
[9]   Biology and treatment of neuroblastoma [J].
Castleberry, RP .
PEDIATRIC CLINICS OF NORTH AMERICA, 1997, 44 (04) :919-&
[10]  
CHOU J, 1988, DOSE EFFECT ANAL MIC