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首页> 外文期刊>Molecular pharmacology. >Using the national cancer institute anticancer drug screen to assess the effect of MRP expression on drug sensitivity profiles.
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Using the national cancer institute anticancer drug screen to assess the effect of MRP expression on drug sensitivity profiles.

机译：使用美国国家癌症研究所的抗癌药物筛选评估MRP表达对药物敏感性的影响。

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The MRP gene contributes to one form of multidrug resistance. To identify drugs interacting with MRP, we measured MRP mRNA expression by quantitative PCR in 60 cell lines of the National Cancer Institute Anticancer Drug Screen. Expression was detected in all cell lines (highest in lung carcinomas and central nervous system tumors) with a range of 14-fold. A mean graph of MRP mRNA levels was constructed to determine Pearson correlation coefficients (PCCs) with mean graphs of >40,000 compounds using the COMPARE analysis. Only 20 compounds had PCCs of >/=0.500. The PCCs for VP-16, doxorubicin, and vincristine were 0.008, 0.13, and 0.257, respectively. Initially, 36 compounds with PCCs of >/=0.428 were analyzed using two MRP-overexpressing cell lines; low levels of cross-resistance was demonstrated for 23 compounds (1.3-9.4-fold). Twenty-four compounds also were available for further studies. Using a fluorescence activated cell sorter assay to measure competition of calcein efflux from MRP-overexpressing cells, 10 compounds were found to increase calcein retention by >/=2-fold. Ten compounds also were able to reduce ATP-dependent [3H]LTC4 transport into vesicles from MRP-overexpressing cells. These results contrast with previous studies with MDR-1 in which high correlations were found and confirmed for a large number of compounds. Although other assays may be more revealing, in these unselected cell lines, MRP mRNA expression was a poor predictor of drug sensitivity. This raises the possibility that other factors, including conjugating enzymes, glutathione levels, or other transporters, confound the MRP effect.
机译：MRP基因有助于一种多药耐药性。为了鉴定与MRP相互作用的药物，我们在国家癌症研究所抗癌药物筛选的60个细胞系中通过定量PCR测量了MRP mRNA的表达。在所有细胞系中检测到表达（在肺癌和中枢神经系统肿瘤中最高），表达范围为14倍。使用COMPARE分析，构建MRP mRNA水平的均值图以确定Pearson相关系数（PCC），其中> 40,000种化合物的均值图。只有20种化合物的PCC> / = 0.500。 VP-16，阿霉素和长春新碱的PCC分别为0.008、0.13和0.257。最初，使用两种过表达MRP的细胞系分析了PCC> / = 0.428的36种化合物。证明了23种化合物的低水平交叉电阻（1.3-9.4倍）。 24种化合物也可用于进一步研究。使用荧光激活的细胞分选测定法测量钙黄绿素从过表达MRP的细胞中流出的竞争，发现10种化合物使钙黄绿素的保留增加了> / = 2倍。十种化合物还能够减少ATP依赖的[3H] LTC4从过表达MRP的细胞进入囊泡的过程。这些结果与以前对MDR-1的研究形成了鲜明对比，在MDR-1中，对大量化合物发现并证实了高度相关性。尽管其他测定可能更能揭示问题，但在这些未选择的细胞系中，MRP mRNA表达不能很好地预测药物敏感性。这增加了其他因素（包括结合酶，谷胱甘肽水平或其他转运蛋白）混淆MRP效应的可能性。

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