Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma

被引:49
作者
Andreadis, Charalambos
Gimotty, Phyllis A.
Wahl, Peter
Hammond, Rachel
Houldsworth, Jane
Schuster, Stephen J.
Rebbeck, Timothy R.
机构
[1] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA
[2] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA
[3] Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA
关键词
D O I
10.1182/blood-2006-09-047621
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Standard chemotherapy fails in 40% to 50% of patients with diffuse large B-cell lymphoma (DLBCL). Some of these failures can be salvaged with high-dose regimens, suggesting a role for drug resistance in this disease. We examined the expression of genes in the glutathione (GSH) and ATP-dependent transporter (ABC) families in 2 independent tissue-based expression microarray datasets obtained prior to therapy from patients with DLBCL. Among genes in the GSH family, glutathione peroxidase 1 (GPX1) had the most significant adverse effect on disease-specific overall survival (dOS) in the primary dataset (n = 130) (HR: 1.68; 95% Cl: 1.26-2.22; P < .001). This effect remained statistically significant after controlling for biologic signature, LLMPP cell-of-origin signature, and IPI score, and was confirmed in the validation dataset (n = 39) (HR: 1.7; 95% CI: 1.05-2.8; P = .033). Recursive partitioning identified a group of patients with low-level expression of GPX1 and multidrug resistance 1 (MDR1; ABCB1) without early treatment failures and with superior dOS (P < .001). Overall, our findings suggest an important association of oxidative-stress defense and drug elimination with treatment failure in DLBCL and identify GPX1 and ABCB1 as potentially powerful biomarkers of early failure and disease-specific survival.
引用
收藏
页码:3409 / 3416
页数:8
相关论文
共 49 条
[1]  
ARMITAGE JO, 2004, DIFFUSE NONHODGKINS, P427
[2]   DOXORUBICIN-INDUCED LIPID-PEROXIDATION AND GLUTATHIONE-PEROXIDASE ACTIVITY IN TUMOR-CELL LINES SELECTED FOR RESISTANCE TO DOXORUBICIN [J].
BENCHEKROUN, MN ;
POURQUIER, P ;
SCHOTT, B ;
ROBERT, J .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1993, 211 (1-2) :141-146
[3]   SUPEROXIDE-DISMUTASE, GLUTATHIONE-PEROXIDASE AND CATALASE IN THE RED-CELLS OF PATIENTS WITH MALIGNANT-LYMPHOMA [J].
BEWICK, M ;
COUTIE, W ;
TUDHOPE, GR .
BRITISH JOURNAL OF HAEMATOLOGY, 1987, 65 (03) :347-350
[4]   EXPRESSION OF HUMAN GLUTATHIONE S-TRANSFERASES IN SACCHAROMYCES-CEREVISIAE CONFERS RESISTANCE TO THE ANTICANCER DRUGS ADRIAMYCIN AND CHLORAMBUCIL [J].
BLACK, SM ;
BEGGS, JD ;
HAYES, JD ;
BARTOSZEK, A ;
MURAMATSU, M ;
SAKAI, M ;
WOLF, CR .
BIOCHEMICAL JOURNAL, 1990, 268 (02) :309-315
[5]   Triggering and modulation of apoptosis by oxidative stress [J].
Chandra, J ;
Samali, A ;
Orrenius, S .
FREE RADICAL BIOLOGY AND MEDICINE, 2000, 29 (3-4) :323-333
[6]   Glutathione S-transferase Mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1 [J].
Cho, SG ;
Lee, YH ;
Park, HS ;
Ryoo, K ;
Kang, KW ;
Park, J ;
Eom, SJ ;
Kim, MJ ;
Chang, TS ;
Choi, SY ;
Shim, J ;
Kim, Y ;
Dong, MS ;
Lee, MJ ;
Kim, SG ;
Ichijo, H ;
Choi, EJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (16) :12749-12755
[7]  
DIRVEN HAAM, 1994, CANCER RES, V54, P6215
[8]   Activation of the p38 signaling pathway by heat shock involves the dissociation of glutathione S-transferase Mu from Ask1 [J].
Dorion, S ;
Lambert, H ;
Landry, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (34) :30792-30797
[9]  
Doroshow JH, 2001, CANC CHEMOTHERAPY BI, P500
[10]  
ELIAS L, 1978, CANCER, V42, P1705, DOI 10.1002/1097-0142(197810)42:4<1705::AID-CNCR2820420408>3.0.CO