Beck J, Handgretinger R, Dopfer R, Klingebiel T, Niethammer D, Gekeler V
Universitäts-Kinderklinik, Tübingen, Germany.
Br J Haematol. 1995 Feb;89(2):356-63. doi: 10.1111/j.1365-2141.1995.tb03312.x.
In a series of 60 ALL samples drawn during different stages of the disease we used a cDNA-PCR approach to analyse the relative mRNA levels of the MDR-associated genes encoding mdr1/P-glycoprotein, mrp, and the topoisomerase II isozymes alpha and beta. Expression analysis of the cyclin A gene was included to examine cellular proliferation activity. The expression of gapdh served as an internal standard. Calculating the mean values we found: (i) a distinctly lower mdr1 gene expression in primary ALL and first relapses compared to bone marrow from healthy donors, (ii) no change in mdr1 and mrp, but a decreased topoisomerase II alpha gene expression in first relapses of ALL compared to the primary leukaemia, and (iii) increased mdr1 and mrp levels combined to decreased topoisomerase II alpha levels in recurrent relapses of ALL showing significant correlations (mdr1/mrp: rs = +0.6833, P < 0.05; mdr1/topoII alpha: rs = -0.6727, P < 0.05). The expression of the topoisomerase II alpha gene was correlated to that of cyclin A, indicating a link of its expression to cellular proliferation. Our findings suggest that a multifactorial MDR including mrp appears particularly in recurrent relapses of ALL, which often do not respond to chemotherapy. Nonetheless, some individual samples showed gene expression levels very different from the mean values calculated for a particular state of the leukaemia, indicating the need of an individual expression analysis of MDR-associated genes.
在一系列60个取自疾病不同阶段的急性淋巴细胞白血病（ALL）样本中，我们采用cDNA - PCR方法分析了编码mdr1/P - 糖蛋白、多药耐药相关蛋白（mrp）以及拓扑异构酶II同工酶α和β的多药耐药相关基因的相对mRNA水平。纳入细胞周期蛋白A基因的表达分析以检测细胞增殖活性。甘油醛 - 3 - 磷酸脱氢酶（gapdh）的表达作为内参。计算平均值后我们发现：（i）与健康供体的骨髓相比，原发性ALL和首次复发时mdr1基因表达明显较低；（ii）ALL首次复发时，mdr1和mrp无变化，但拓扑异构酶IIα基因表达相较于原发性白血病有所降低；（iii）ALL复发时mdr1和mrp水平升高，同时拓扑异构酶IIα水平降低，显示出显著相关性（mdr1/mrp：rs = +0.6833，P < 0.05；mdr1/拓扑异构酶IIα：rs = -0.6727，P < 0.05）。拓扑异构酶IIα基因的表达与细胞周期蛋白A的表达相关，表明其表达与细胞增殖存在联系。我们的研究结果表明，包括mrp在内的多因素多药耐药尤其出现在ALL的复发中，而这些复发通常对化疗无反应。尽管如此，一些个体样本显示基因表达水平与针对白血病特定状态计算出的平均值差异很大，这表明需要对多药耐药相关基因进行个体表达分析。
