Introduction MDR1 1 4 3 5 7 8 13 MDR1 MRP1 LRP BCRP Patients and methods Patients 14 15 14 14 This study was approved by the ethics committees of the participating institutions and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients before randomization. Methods 3 16 MDR1, MRP1, LRP, and BCRP mRNA analysis 11 MDR1 MRP1 LRP BCRP Definition of endpoints 14 Statistical analysis α MDR1 MRP1 LRP BCRP χ 2 χ 2 17 MDR1 MRP1 LRP BCRP 18 MDR1 BCRP MDR1 BCRP 19 MDR1 BCRP + 20 21 p p Results p p p p 14 MDR1 MRP1 LRP BCRP 1 p MDR1 MRP1 LRP BCRP 1 p p Table 1 Comparison between patients with or without data available for expression of the drug resistance genes   Drug resistance genes evaluated   N N N p Number of patients 154 265 419  Patient characteristics Median age, (range) 67 (60–85) 68 (58–85) 67 (58–85) 0.52 Sex    0.26  Male 86 (56) 163 (62) 249 (59)   Female 68 (44) 102 (38) 170 (41)  Secondary AML 31 (20) 73 (28) 104 (25) 0.09 9 19.1 (0.1–389) 5.6 (0.5–300) 8.9 (0.1–389) 0.001 N 146 243 389  + 32.5 (0.1–97.9) 29.7 (0.1–93.7) 30.3 (0.1–97.9) 0.50 N 152 157 309  a    0.12  Favorable 3 (3) 2 (1) 5 (2)   Intermediate 90 (80) 132 (73) 222 (76)   Unfavorable 19 (17) 47 (26) 66 (23)   No data 42 (n.i.) 84 (n.i.) 126 (n.i.)  Treatment arm randomized    0.02  DNR/ara-C 66 (43) 145 (55) 211 (50)   DNR/ara-C +PSC-833 88 (57) 120 (45) 208 (50)  Treatment outcome CR rate, % (95% CI) 52 (44–60) 50 (44–56) 51 (46–56) 0.73 EFS, % (95% CI)    0.72  1 year 23 (17–30) 23 (18–28) 23 (19–27)   5 years 9 (5–14) 7 (4–11) 8 (5–11)  DFS, % (95% CI)    0.81  1 year 38 (27–48) 39 (31–48) 39 (32–45)   5 years 17 (10–26) 14 (9–21) 15 (11–21)  OS, % (95% CI)    0.31  1 year 42 (34–50) 41 (35–46) 41 (36–46)   5 years 14 (9–20) 8 (5–12) 10 (7–14)  The results indicate that, apart from WBC count, there are no differences between the two subgroups. N n.i. a 14 2 MRP1 LRP MDR1 BCRP MDR1 BCRP MRP1 LRP 2 BCRP p MRP1 LRP p 2 MDR1 p 22 Table 2 MDR1 BCRP   mRNA expression of MDR1 MRP1 LRP BCRP MDR1 BCRP Characteristic  Age 0.15 −0.01 −0.09 0.09 0.07 (153) (153) (153) (137) (147)  Secondary AML 0.06 −0.22** −0.21** 0.19* 0.12 (153) (153) (153) (137) (147)  WBC count −0.17* 0.28*** 0.36*** −0.36*** −0.35*** (145) (145) (145) (131) (139) + 0.54*** 0.14 −0.08 0.17* 0.27** (151) (151) (151) (135) (145)  Unfavorable  0.11 −0.05 −0.23* 0.13 0.10  Cytogenetic risk (111) (111) (111) (98) (106) Unfavorable cytogenetic risk was defined by the presence of monosomies or deletions of chromosomes 5 or 7, abnormalities of the long arm of chromosome 3(q21;q6), t(6;9), abnormalities involving the long arm of chromosome 11 (11q23), or complex cytogenetic abnormalities (defined as at least three unrelated cytogenetic abnormalities in one clone) Each cell displays the Spearman rank correlation coefficient between two variables and, between brackets, the number of patients with both variables available. p p p MDR1 BCRP p MRP1 LRP p 1 BCRP MRP1 BCRP LRP p 1 BCRP MDR1 p 9 9 p MDR1 BCRP MDR1 BCRP p 2 Fig. 1 MDR1 MRP1 LRP BCRP dot p x y X X r p p MDR1 BCRP p MRP1 LRP BCRP MRP1 LRP  MDR1 MDR1 p MRP1 LRP BCRP 1 MDR1 MDR1 p MDR1 p MDR1 BCRP 3 2 Statistical analysis MDR1 BCRP p 3 p p p p Table 3 Prognostic value of drug resistance gene expression w.r.t. CR rate, EFS, DFS from CR, and OS   CR rate EFS DFS OS OR 95% CI p HR 95% CI p HR 95% CI p HR 95% CI p MDR1              Univariate 0.75 0.61–0.93 0.009 1.14 1.03–1.27 0.01 1.13 0.97–1.30 0.11 1.16 1.05–1.29 0.004  Adjusted 0.77 0.58–1.03 0.08 1.05 0.91–1.21 0.48 0.95 0.77–1.18 0.67 1.00 0.87–1.16 0.97 MRP1              Univariate 1.06 0.83–1.35 0.63 1.02 0.90–1.15 0.79 1.07 0.89–1.29 0.47 1.11 0.97–1.26 0.12  Adjusted 1.22 0.90–1.66 0.20 1.00 0.87–1.15 0.98 1.12 0.92–1.37 0.26 1.05 0.91–1.21 0.54 LRP              Univariate 1.16 0.94–1.43 0.16 0.95 0.86–1.06 0.36 0.98 0.84–1.14 0.79 0.97 0.87–1.08 0.60  Adjusted 1.22 0.93–1.61 0.15 0.99 0.87–1.12 0.83 1.06 0.89–1.27 0.52 0.98 0.86–1.12 0.78 BCRP              Univariate 0.84 0.66–1.06 0.14 1.04 0.91–1.18 0.58 0.95 0.77–1.16 0.60 0.96 0.84–1.10 0.58  Adjusted 0.79 0.59–1.06  0.12 0.99 0.86–1.14 0.92 0.84 0.66–1.06 0.14 0.90 0.77–1.05 0.19 MDR1 BCRP              Univariate 0.38 0.18–0.80 0.01 1.63 1.11–2.37 0.01 1.65 0.90–3.01 0.11 1.47 1.00–2.16 0.05  Adjusted 0.37 0.15–0.92  0.03 1.53 0.98–2.38 0.06 1.37 0.67–2.82 0.39 1.16 0.74–1.83 0.51 + MDR1 MRP1 LRP BCRP MDR1 BCRP Fig. 2 MDR1 BCRP mRNA a b c pos MDR1 BCRP other  Discussion 14 9 11 23 MRP1 LRP BCRP 3 4 5 7 24 27 BCRP BCRP 10 23 28 BCRP BCRP BCRP 29 19 BCRP BCRP BCRP MDR1 9 11 28 MDR1 BCRP 19 28 19 BCRP MDR1 MDR1 BCRP MDR1/BCRP p MDR1 BCRP 28 BCRP MDR1 BCRP MDR1 30 MDR1 BCRP MRP1 LRP MDR1 BCRP 13 19 BCRP MDR1 31 34 BCRP BCRP + − + − 12 35 BCRP MDR1 36 19 BCRP/MDR1 3 2 BCRP BCRP BCRP 11 29 37 BCRP MDR1 BCRP BCRP BCRP MDR1