TRANSGENIC MICE THAT EXPRESS THE HUMAN MULTIDRUG-RESISTANCE GENE IN BONE-MARROW ENABLE A RAPID IDENTIFICATION OF AGENTS THAT REVERSE DRUG-RESISTANCE

被引:150
作者
MICKISCH, GH
MERLINO, GT
GALSKI, H
GOTTESMAN, MM
PASTAN, I
机构
[1] NCI,MOLEC BIOL LAB,BLDG 37,ROOM 4E16,BETHESDA,MD 20892
[2] NCI,CELL BIOL LAB,BETHESDA,MD 20892
[3] NCI,DIV CANC BIOL DIAGN & CTR,BETHESDA,MD 20892
关键词
CHEMOSENSITIZERS; DAUNOMYCIN; TAXOL/(R)-VERAPAMIL; CHEMOTHERAPY;
D O I
10.1073/pnas.88.2.547
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The development of preclinical models for the rapid testing of agents that circumvent multidrug resistance in cancer is a high priority of research on drug resistance. A common form of multidrug resistance in human cancer results from expression of the MDR1 gene, which encodes a M(r)170,000 glycoprotein that functions as a plasma membrane energy-dependent multidrug efflux pump. We have engineered transgenic mice that express this multidrug transporter in their bone marrow and demonstrated that these animals are resistant to leukopenia by a panel of anticancer drugs including anthracyclines, vinca alkaloids, etoposide, taxol, and actinomycin D. Differential leukocyte counts indicate that both neutrophils and lymphocytes are protected. Drugs such as cisplatin, methotrexate, and 5-fluorouracil, which are not handled by the multidrug transporter, produce bone marrow suppression in both normal and transgenic mice. The resistance conferred by the MDR1 gene can be circumvented in a dose-dependent manner by simultaneous administration of agents previously shown to be inhibitors of the multidrug transporter in vitro, including verapamil isomers, quinidine, and quinine. Verapamil and quinine, both at levels suitable for human trials that produced only partial sensitization of the MDR1-transgenic mice, were fully sensitizing when used in combination. We conclude that MDR1-transgenic mice provide a rapid and reliable system to determine the bioactivity of agents that reverse multidrug resistance in animals.
引用
收藏
页码:547 / 551
页数:5
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