Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line.
Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line.
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DOI：
10.1038/bjc.1991.202
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发表时间：
1991-06
影响因子：
8.8
通讯作者：
Trent JM
中科院分区：
文献类型：
--
作者：
Taylor CW;Dalton WS;Parrish PR;Gleason MC;Bellamy WT;Thompson FH;Roe DJ;Trent JM
我们分别通过体外慢性暴露于阿霉素（MCF7/D40细胞系）和米托蒽醌（MCF7/Mitox细胞系），选择了MCF7人乳腺癌细胞系的两种耐药变体。细胞系在倍增时间、DNA合成期和细胞大小等生长特性上相似。对米托蒽醌耐药仅使对阿霉素部分耐药；而对阿霉素选择的耐药似乎赋予了对米托蒽醌的完全耐药。两种药剂均对长春花生物碱产生交叉抗性。MCF7/D40细胞表现出典型的多药耐药表型，p -糖蛋白表达，相对于亲本系药物积累减少，维拉帕米逆转药物积累和耐药。MCF7/Mitox细胞同样表现出对多种药物的耐药，但与MCF7/D40细胞相比，免疫印迹和RNA印迹分析显示，MCF7/Mitox细胞不表达p -糖蛋白。与亲本细胞相比，MCF7/Mitox细胞的净药物积累减少，但维拉帕米对药物积累和体外耐药没有选择性调节。与MCF7/S细胞系相比，MCF7/D40和MCF7/Mitox细胞系中米托蒽醌的外排均增强。我们得出结论，两种耐药细胞系具有不同的减少药物积累的机制。
We selected two drug resistant variants of the MCF7 human breast cancer cell line by chronic in vitro exposure to doxorubicin (MCF7/D40 cell line) and mitoxantrone (MCF7/Mitox cell line), respectively. The cell lines are similar in growth characteristics including doubling time, DNA synthetic phase and cell size. Resistance to mitoxantrone conferred only partial resistance to doxorubicin; whereas resistance selected for doxorubicin appeared to confer complete resistance to mitoxantrone. Both agents selected for cross resistance to the Vinca alkaloids. MCF7/D40 cells display a classic-multi-drug resistance phenotype with expression of P-glycoprotein, decreased drug accumulation relative to the parental line and reversal of drug accumulation and drug resistance by verapamil. MCF7/Mitox cells likewise display resistance to multiple drugs, but in contrast to MCF7/D40 cells do not express P-glycoprotein by immunoblot or RNA blot analysis. Net drug accumulation in MCF7/Mitox cells was decreased relative to the parental cells but there was no selective modulation of drug accumulation or in vitro drug resistance by the addition of verapamil. Efflux of mitoxantrone was enhanced in both the MCF7/D40 and MCF7/Mitox cell lines relative to the MCF7/S cell line. We conclude that the two drug resistant cell lines have different mechanisms of decreased drug accumulation.