van der Pol Marjolein A, Broxterman Henk J, Pater Jennie M, Feller Nicole, van der Maas Martin, Weijers Geert W D, Scheffer George L, Allen John D, Scheper Rik J, van Loevezijn Arnold, Ossenkoppele Gert J, Schuurhuis Gerrit J
Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Haematologica. 2003 Feb;88(2):134-47.
Relapse is common in acute myeloid leukemia (AML) because of persistence of minimal residual disease (MRD). ABC-transporters P-glycoprotein (Pgp) and multidrug resistance protein (MRP), are thought to contribute to treatment failure, while it is unknown whether breast cancer resistance protein (BCRP) does so. However, whether up-regulation of pump activity or selection of subpopulations with higher pump activity occurs during chemotherapy is unclear. The aim of this study was to elucidate whether ABC-transporter function changes during the course of disease.
MRD cells were identified using leukemia-associated phenotypes combined with a fluorescent probe assay with substrate/modulator: Syto16/ PSC833 (Pgp), calcein-AM/probenecid (MRP) and BODIPY-prazosin/Ko143 (BCRP); efflux profiles were directly compared with blasts at diagnosis and relapse from the same patient.
At diagnosis BCRP activity was undetectable in AML blasts from 23/26 cases, while Pgp activity was present in 36/45 and MRP activity in 26/44 of the cases. Furthermore, no subpopulations of blasts with considerably higher drug efflux capacities were found. Overall, no consistent changes were observed at follow-up [during chemotherapy (n=20), MRD (n=37), relapse (n=26))] in forty-five patients, the mean activities (as percentages of values at diagnosis) were 97% (Pgp), 103% (MRP) and 102% (BCRP).
Emergence of MRD is thus not accompanied by either upregulation of ABC-transporter function during or after chemotherapy or by selection of pre-existing highly resistant subpopulations. The prognostic value of Pgp and MRP is, therefore, likely related to drug efflux capacity homogeneously distributed in the whole blast population, while BCRP probably has a limited function in drug efflux-related resistance in AML.
由于微小残留病（MRD）的持续存在，复发在急性髓系白血病（AML）中很常见。ABC转运蛋白P-糖蛋白（Pgp）和多药耐药蛋白（MRP）被认为是导致治疗失败的原因，而乳腺癌耐药蛋白（BCRP）是否如此尚不清楚。然而，化疗期间泵活性上调或具有更高泵活性的亚群选择是否发生尚不清楚。本研究的目的是阐明ABC转运蛋白功能在疾病过程中是否发生变化。
使用白血病相关表型结合底物/调节剂荧光探针检测法鉴定MRD细胞：Syto16/PSC833（Pgp）、钙黄绿素-AM/丙磺舒（MRP）和BODIPY-哌唑嗪/Ko143（BCRP）；将流出曲线直接与同一患者诊断时和复发时的原始细胞进行比较。
在诊断时，23/26例AML原始细胞中未检测到BCRP活性，而36/45例中存在Pgp活性，26/44例中存在MRP活性。此外，未发现具有明显更高药物流出能力的原始细胞亚群。总体而言，在45例患者的随访期间[化疗期间（n=20）、MRD（n=37）、复发（n=26）]未观察到一致变化，平均活性（作为诊断时值的百分比）分别为97%（Pgp）、103%（MRP）和102%（BCRP）。
因此，MRD的出现既不伴有化疗期间或化疗后ABC转运蛋白功能上调，也不伴有预先存在的高耐药亚群的选择。因此，Pgp和MRP的预后价值可能与整个原始细胞群体中均匀分布的药物流出能力有关，而BCRP在AML的药物流出相关耐药中可能具有有限的功能。
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