P-GLYCOPROTEIN EXPRESSION AND SCHEDULE DEPENDENCE OF ADRIAMYCIN CYTOTOXICITY IN HUMAN COLON-CARCINOMA CELL-LINES
P-GLYCOPROTEIN EXPRESSION AND SCHEDULE DEPENDENCE OF ADRIAMYCIN CYTOTOXICITY IN HUMAN COLON-CARCINOMA CELL-LINES
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DOI：
10.1002/ijc.2910490512
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发表时间：
1991-11-11
影响因子：
6.4
通讯作者：
BATES, SE
中科院分区：
文献类型：
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作者：
LAI, GM;CHEN, YN;BATES, SE
研究了四种人结肠癌细胞系（SW 620、LS 180、DLD-1和HCT-15）和具有不同程度P-糖蛋白表达的阿霉素耐药亚系，以评估人结肠癌阿霉素耐药的可逆性。研究了两组细胞系。在第一，包括一系列阿霉素耐药SW 620和DLD-1亚系，并在父母HCT-15细胞，P-糖蛋白在阿霉素耐药性的主要作用，证明阿霉素耐药性，多药耐药基因mdr-1及其产物，P-糖蛋白（Pgp），减少药物积累和可逆性维拉帕米之间的相关性。在这些细胞系中，需要增加维拉帕米的剂量才能完全逆转不断增加的耐药性水平。在第二组中，包括亲本SW 620、DLD-1和LS 180细胞以及阿霉素选择的LS 180亚系，P-糖蛋白在阿霉素抗性中不具有主要作用。阿霉素细胞毒作用的时间依赖性与P-糖蛋白的耐药调节作用有关。在P-糖蛋白是阿霉素耐药的主要决定因素的细胞系中，药物暴露与3小时相比，当细胞被处理7天时，达到给定的细胞杀伤百分比所需的浓度（定义为浓度和处理时间的乘积）减少了9倍。通过比较，在P-糖蛋白起较小作用的细胞系中，在连续治疗的条件下，达到给定的杀灭百分比所必需的药物暴露增加。在一些人结肠癌细胞系中，Pgp似乎在对阿霉素的耐药性中起重要作用，这可以通过使用Pgp的竞争性抑制剂来克服。在具有P-糖蛋白介导的耐药的细胞系中观察到的连续治疗的敏感性增加表明，通过连续输注给药在逆转主要由P-糖蛋白介导的临床耐药方面可能是有价值的。
Four human colon cancer cell lines (SW620, LS 180, DLD-1, and HCT-15) and Adriamycin-resistant sub-lines with varying degrees of P-glycoprotein expression were studied to evaluate the reversibility of Adriamycin resistance in human colon cancer. Two groups of cell lines were studied. In the first, including a series of Adriamycin-resistant SW620 and DLD-1 sub-lines, and in parental HCT-15 cells, P-glycoprotein has a major role in Adriamycin resistance, as evidenced by a correlation between Adriamycin resistance, expression of the multidrug-resistance gene mdr-1 and its product, P-glycoprotein (Pgp), decreased drug accumulation and reversibility by verapamil. In these cell lines, increasing doses of verapamil are required to fully reverse increasing levels of resistance. In the second group, including parental SW620, DLD-1 and LS 180 cells and Adriamycin-selected LS 180 sub-lines, P-glycoprotein does not have a major role in Adriamycin resistance. There was correlation between the schedule dependence of Adriamycin cytotoxicity and the role of P-glycoprotein in modulating resistance. In the cell lines in which P-glycoprotein was a major determinant of Adriamycin resistance, the drug exposure (defined as the product of the concentration and the time of treatment) needed to achieve a given percent cell kill was reduced as much as 9-fold when cells were treated for 7 days as compared with 3 hr. By comparison, in cell lines in which P-glycoprotein played a lesser role, the drug exposure necessary to achieve a given percent kill increased under conditions of continuous treatment. In some human colon carcinoma cell lines Pgp appears to play a significant role in resistance to Adriamycin, and this can be overcome by the use of competitive inhibitors of Pgp. The increased sensitivity with continuous treatment observed in cell lines with P-glycoprotein-mediated resistance suggests that administration of drugs by continuous infusion may be valuable in reversing clinical drug resistance mediated predominantly by P-glycoprotein.