Mickisch G H, Merlino G T, Galski H, Gottesman M M, Pastan I
Division of Cancer Biology Diagnosis and Centers, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):547-51. doi: 10.1073/pnas.88.2.547.
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 Mr 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.
开发用于快速测试克服癌症多药耐药性药物的临床前模型是耐药性研究的重中之重。人类癌症中常见的一种多药耐药形式是由MDR1基因的表达引起的，该基因编码一种分子量为170,000的糖蛋白，其作为质膜能量依赖性多药外排泵发挥作用。我们构建了在骨髓中表达这种多药转运蛋白的转基因小鼠，并证明这些动物对包括蒽环类药物、长春花生物碱、依托泊苷、紫杉醇和放线菌素D在内的一组抗癌药物引起的白细胞减少具有抗性。白细胞分类计数表明中性粒细胞和淋巴细胞均受到保护。顺铂、甲氨蝶呤和5-氟尿嘧啶等不由多药转运蛋白处理的药物在正常小鼠和转基因小鼠中均会产生骨髓抑制。通过同时给予先前在体外已证明是多药转运蛋白抑制剂的药物，包括维拉帕米异构体、奎尼丁和奎宁，MDR1基因赋予的抗性可以以剂量依赖的方式被克服。维拉帕米和奎宁在适合人体试验的水平下仅使MDR1转基因小鼠产生部分致敏作用，但联合使用时则具有完全致敏作用。我们得出结论，MDR1转基因小鼠提供了一个快速可靠的系统，用于确定在动物中逆转多药耐药性的药物的生物活性。
