Zhan Z, Sandor V A, Gamelin E, Regis J, Dickstein B, Wilson W, Fojo A T, Bates S E
National Institutes of Health, National Cancer Institute, Medicine Branch, Bethesda, MD 20892, USA.
Blood. 1997 May 15;89(10):3795-800.
Previous work investigating the role of MDR-1 overexpression in relapsed and refractory lymphoma led us to investigate a possible role for multidrug resistance-associated protein (MRP) as a cause of resistance in patients who did not overexpress MDR-1. A quantitative polymerase chain reaction (PCR) method for measuring MRP expression was validated. Immunoblot analysis suggested that no major discrepancy was present between mRNA expression and protein levels. MRP levels were found to be independent of sample tumor content by immunophenotyping, suggesting that the presence of normal cells had no significant impact on measurements of MRP expression. We evaluated MRP in 55 biopsy samples from 40 patients with refractory lymphoma enrolled on a trial of infusional chemotherapy (EPOCH). Pre- and post-EPOCH samples were available from 15 patients. MRP levels were also evaluated in 16 newly diagnosed, untreated lymphoma patient samples. No significant difference in MRP mRNA expression was noted between pre- and post-EPOCH groups. Also, MRP levels in the newly diagnosed patient samples were not significantly different from either pre- or post-EPOCH groups. Two of 15 paired pre- and post-EPOCH patient samples exhibited overexpression of MRP after EPOCH chemotherapy, with measured increases of 10-fold and 18-fold. We conclude that MRP overexpression is not responsible for non-P-glycoprotein (Pgp)-mediated drug resistance in the majority of these patients, although it may be important in a subset of patients. Defining this subset prospectively could aid in the development of clinical trials of MRP modulation in drug-resistant lymphoma.
先前关于多药耐药蛋白1（MDR-1）过表达在复发难治性淋巴瘤中作用的研究，促使我们去探究多药耐药相关蛋白（MRP）在未过表达MDR-1的患者中作为耐药原因的可能作用。一种用于测量MRP表达的定量聚合酶链反应（PCR）方法得到了验证。免疫印迹分析表明，mRNA表达与蛋白水平之间不存在重大差异。通过免疫表型分析发现，MRP水平与样本肿瘤含量无关，这表明正常细胞的存在对MRP表达的测量没有显著影响。我们对40例接受灌注化疗（EPOCH）试验的难治性淋巴瘤患者的55份活检样本中的MRP进行了评估。15例患者有EPOCH治疗前后的样本。还对16例新诊断的未经治疗的淋巴瘤患者样本中的MRP水平进行了评估。EPOCH治疗前后组之间在MRP mRNA表达上未发现显著差异。此外，新诊断患者样本中的MRP水平与EPOCH治疗前或治疗后组均无显著差异。15例EPOCH治疗前后配对的患者样本中有2例在EPOCH化疗后出现MRP过表达，测量到的增加倍数分别为10倍和18倍。我们得出结论，在这些患者中的大多数，MRP过表达并非非P-糖蛋白（Pgp）介导的耐药原因，尽管在一部分患者中可能很重要。前瞻性地确定这部分患者可能有助于开展耐药淋巴瘤中MRP调节的临床试验。
