Pérez-Simón J A, Valverde B, Martínez A, Tabernero D, Almeida J, Gutierrez N, San Miguel J F, Orfao A
Servicio de Hematología, Hospital Universitario de Salamanca, Spain.
Cytometry. 1999 Feb 15;38(1):24-9.
Although a variable proportion of multiple myeloma patients can achieve response with conventional chemotherapy, residual tumor cells, which are refractory, finally reemerge leading to disease progression. The expression of the multidrug resistance protein (MDR1) has been one of the most extensively explored mechanisms of drug resistance and has been related to a poor response to chemotherapy in several human tumors. Nevertheless, a careful analysis of the literature on MDR1 expression in multiple myeloma (MM) shows the existence of disturbing discrepancies as regards both the incidence of MDR1 over-expression and its clinical value. A prerequisite for the assessment of MDR1 in tumor cells should be the identification of the neoplastic cells present in the sample. This is particularly important in MM, where the percentage of tumor cells in bone marrow (BM) is relatively low. In the present study we have analyzed the functional expression of MDR1 in BM plasma cells (PC), from a group of 40 untreated MM patients. For that purpose, the rhodamine 123 efflux assay was used in combination with specific staining for plasma cells (CD38 strong+). The mean fluorescence channel (MFC) of rhodamine 123 in myelomatous PC from MM patients was 311 and 110 after incubating cells with this fluorochrome for 15 and 60 min, respectively. The median percentage of rhodamine 123 elimination by BM PC was of 61% (range: 0.29 to 88%). Upon analyzing the relationship between the ability of myelomatous PC to eliminate rhodamine 123 and other clinical and biological disease characteristics we found that, within the group of patients displaying high MDR1 expression (>61% rhodamine efflux), there was a higher incidence of cases with bone disease (P = 0.014) and advanced clinical stages (P = 0.031), greater calcium (P = 0.007) and creatinine serum levels (P = 0.061), and lower levels of albumin in serum (P = 0.015). All these parameters are usually associated with a poor prognosis. When we analyzed the possible relationship between the ability of BM PC to eliminate rhodamine 123 and the presence of numerical chromosome abnormalities we observed that a low MDR1 expression was related to a higher incidence of trisomies of chromosomes 6 and 17, although these differences did not reach statistical significance (P = 0.06). In spite of these associations, from the prognostic point of view, MDR1 expression did not correlate with other relevant prognostic factors, response to treatment (P = 0.38) or overall survival (P = 0.12).
尽管可变比例的多发性骨髓瘤患者可通过传统化疗获得缓解，但残留的难治性肿瘤细胞最终会重新出现，导致疾病进展。多药耐药蛋白（MDR1）的表达一直是研究最为广泛的耐药机制之一，并且与多种人类肿瘤化疗反应不佳有关。然而，仔细分析关于多发性骨髓瘤（MM）中MDR1表达的文献会发现，在MDR1过表达的发生率及其临床价值方面存在令人困扰的差异。评估肿瘤细胞中MDR1的一个先决条件应该是识别样本中存在的肿瘤细胞。这在MM中尤为重要，因为骨髓（BM）中肿瘤细胞的百分比相对较低。在本研究中，我们分析了40例未经治疗的MM患者的BM浆细胞（PC）中MDR1的功能性表达。为此，将罗丹明123外排试验与浆细胞特异性染色（CD38强阳性）相结合使用。用这种荧光染料孵育细胞15分钟和60分钟后，MM患者骨髓瘤PC中罗丹明123的平均荧光通道（MFC）分别为311和110。BM PC消除罗丹明123的中位数百分比为61%（范围：0.29至88%）。在分析骨髓瘤PC消除罗丹明123的能力与其他临床和生物学疾病特征之间的关系时，我们发现，在显示高MDR1表达（罗丹明外排>61%）的患者组中，骨病（P = 0.014）和晚期临床分期（P = 0.031）的病例发生率更高，血清钙（P = 0.007）和肌酐水平更高（P = 0.061），血清白蛋白水平更低（P = 0.015）。所有这些参数通常都与预后不良有关。当我们分析BM PC消除罗丹明123的能力与染色体数目异常的存在之间的可能关系时，我们观察到低MDR1表达与6号和17号染色体三体的发生率较高有关，尽管这些差异未达到统计学意义（P = 0.06）。尽管存在这些关联，但从预后角度来看，MDR1表达与其他相关预后因素、治疗反应（P = 0.38）或总生存期（P = 0.12）均无相关性。
