Using the national cancer institute anticancer drug screen to assess the effect of mrp expression on drug sensitivity profiles
Using the national cancer institute anticancer drug screen to assess the effect of mrp expression on drug sensitivity profiles
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DOI：
10.1124/mol.54.5.802
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发表时间：
1998-11-01
影响因子：
3.6
通讯作者：
Fojo, T
中科院分区：
文献类型：
--
作者：
Alvarez, M;Robey, R;Fojo, T
MRP基因导致一种形式的多药耐药性。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MRP mRNA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），范围为14倍。构建MRP mRNA水平的平均图以使用COMPARE分析确定具有> 40，000种化合物的平均图的皮尔逊相关系数（PCC）。只有20种化合物的PCCs大于或等于0.500。VP-16、多柔比星和长春新碱的PCC分别为0.008、0.13和0.257。最初，使用两种MRP过表达细胞系分析了PCC大于或等于0.428的36种化合物;证明了23种化合物的低水平交叉耐药性（1.3-9.4倍）。24种化合物也可用于进一步研究。使用荧光激活细胞分选仪测定来测量来自MRP过表达细胞的钙黄绿素流出的竞争，发现10种化合物使钙黄绿素保留增加大于或等于2倍。10种化合物也能够减少ATP依赖的[（3）H]LTC（4）从MRP过表达细胞转运到囊泡中。这些结果与先前的MDR-1研究形成对比，其中发现并证实了大量化合物的高度相关性。虽然其他检测方法可能更有启发性，但在这些NSCLC细胞系中，MRP mRNA表达是药物敏感性的不良预测因子。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。
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 greater than or equal to 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 greater than or equal to 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 greater than or equal to 2-fold. Ten compounds also were able to reduce ATP-dependent [(3)H]LTC(4) 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.