Evaluation of the clinical relevance of the expression and function of P-glycoprotein, multidrug resistance protein and lung resistance protein in patients with primary acute myelogenous leukemia

2002 ◽  
Vol 26 (2) ◽  
pp. 143-154 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
George Paterakis ◽  
George Androutsos ◽  
Nikolaos Anagnostopoulos ◽  
Athanasios Galanopoulos ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Multidrug Resistance Protein ◽  
Lung Resistance Protein ◽  
P Glycoprotein ◽  
Lung Resistance ◽  
Acute Myelogenous ◽  
Resistance Protein ◽  
And Function

Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1202-1210 ◽  
Author(s):  
Eric Solary ◽  
Bernard Drenou ◽  
Lydia Campos ◽  
Patricia de Crémoux ◽  
Francine Mugneret ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Complete Remission ◽  
Significant Influence ◽  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Myelogenous Leukemia ◽  
P Glycoprotein ◽  
Acute Myelogenous ◽  
The Mean

Abstract Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein–mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These patients randomly received (n = 213) or did not receive (n = 212) a 30 mg/kg/day continuous intravenous infusion of quinine in combination with induction chemotherapy combining idarubicine and cytarabine and, depending on bone marrow examination at day 20, an additional course of cytarabine and mitoxantrone. The mean steady-state quinine concentration was 7.8 mg/L and the mean multidrug resistance reversing activity of serum was 1.96. Complete remission (CR) was obtained in 344 patients (80.9%) without significant influence of quinine. Of the patients in complete remission, 82 were assigned to receive HLA-matched bone marrow transplants, whereas 262 were assigned to 2 courses of intensive consolidation chemotherapy, with or without quinine, depending on initial randomization. The 4-year actuarial overall survival (OS) of the 425 eligible patients was 42.0% ± 2.5%, without significant influence of quinine. Of 160 patients who could be studied, 54 demonstrated rhodamine 123 efflux. In these patients, quinine significantly improved the CR rate from 12 of 25 (48.0%) to 24 of 29 (82.8%) (P = .01). However, there was no significant difference in OS. Neither mdr1 gene nor P-glycoprotein expression influenced the outcome. We conclude that quinine does not improve the survival of adult patients with de novo AML, even though it improves CR rate in a small subgroup of patients defined by rhodamine 123 efflux.

scholarly journals Relationship Between Major Vault Protein/Lung Resistance Protein, Multidrug Resistance-Associated Protein, P-Glycoprotein Expression, and Drug Resistance in Childhood Leukemia

Blood ◽  
1998 ◽  
Vol 91 (6) ◽  
pp. 2092-2098 ◽  
Author(s):  
M.L. den Boer ◽  
R. Pieters ◽  
K.M. Kazemier ◽  
M.M.A. Rottier ◽  
C.M. Zwaan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Major Vault Protein ◽  
Lung Resistance Protein ◽  
P Glycoprotein ◽  
Lung Resistance ◽  
Resistance Protein

Cellular drug resistance is related to a poor prognosis in childhood leukemia, but little is known about the underlying mechanisms. We studied the expression of P-glycoprotein (P-gp), multidrug resistance (MDR)-associated protein (MRP), and major vault protein/lung resistance protein (LRP) in 141 children with acute lymphoblastic leukemia (ALL) and 27 with acute myeloid leukemia (AML) by flow cytometry. The expression was compared between different types of leukemia and was studied in relation with clinical risk indicators and in vitro cytotoxicity of the MDR-related drugs daunorubicin (DNR), vincristine (VCR), and etoposide (VP16) and the non–MDR-related drugs prednisolone (PRD) and L-asparaginase (ASP). In ALL, P-gp, MRP, and LRP expression did not differ between 112 initial and 29 unrelated relapse samples nor between paired initial and relapse samples from 9 patients. In multiple relapse samples, LRP expression was 1.6-fold higher compared with both initial (P = .026) and first relapse samples (P = .050), which was not observed for P-gp and MRP. LRP expression was weakly but significantly related to in vitro resistance to DNR (Spearman's rank correlation coefficient 0.25, P = .016) but not to VCR, VP16, PRD, and ASP. No significant correlations were found between P-gp or MRP expression and in vitro drug resistance. Samples with a marked expression of two or three resistance proteins did not show increased resistance to the tested drugs compared with the remaining samples. The expression of P-gp, MRP, and LRP was not higher in initial ALL patients with prognostically unfavorable immunophenotype, white blood cell count, or age. The expression of P-gp and MRP in 20 initial AML samples did not differ or was even lower compared with 112 initial ALL samples. However, LRP expression was twofold higher in the AML samples (P < .001), which are more resistant to a variety of drugs compared with ALL samples. In conclusion, P-gp and MRP are unlikely to be involved in drug resistance in childhood leukemia. LRP might contribute to drug resistance but only in specific subsets of children with leukemia.

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