Tang-Wai D F, Kajiji S, DiCapua F, de Graaf D, Roninson I B, Gros P
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Biochemistry. 1995 Jan 10;34(1):32-9. doi: 10.1021/bi00001a005.
Possible functional differences between P-glycoproteins (P-gps) encoded by the human MDR1 and mouse mdr1 and mdr3 genes with respect to drug resistance profiles and sensitivity to known modulators have been investigated. For this, the three genes were introduced and overexpressed in the same cellular background, that of Chinese hamster LR73 ovary cells, and drug-resistant clones expressing comparable amounts of the corresponding P-gps were selected under the same conditions. Analysis of the specific drug resistance profiles encoded by each P-gp for colchicine, adriamycin, vinblastine, and actinomycin D revealed overlapping but distinct patterns of drug resistance for the three isoforms. While all three P-gps conferred levels of resistance to vinblastine that did not vary by more than 2.5-fold, each isoform could be clearly distinguished by its capacity to confer resistance to colchicine and actinomycin D. Likewise, the study of structurally related and unrelated P-gp modulators indicated strong isoform-specific differences in the capacity of individual modulators to abrogate vinblastine resistance in the corresponding mdr transfectants. The study of several disubstituted piperazine analogs indicated that minor chemical modifications of the linker region of this modulator had strong effects on the sensitivity profile of each isoform to the modulator. Together, these results indicate that the three P-gp isoforms analyzed have specific and distinguishable functional characteristics with respect to interactions with drugs and modulators. These findings also suggest that P-gp positive murine transplantable tumors should be used with caution in the design and in vivo testing of novel P-gp modulators to be used to reverse multidrug resistance to tumor cells expressing human MDR1.
关于人类MDR1基因以及小鼠mdr1和mdr3基因编码的P-糖蛋白（P-gps）在耐药谱和对已知调节剂敏感性方面可能存在的功能差异，已进行了研究。为此，将这三个基因导入并在中国仓鼠LR73卵巢细胞的相同细胞背景中过表达，在相同条件下选择表达相当量相应P-gps的耐药克隆。对每种P-gp编码的针对秋水仙碱、阿霉素、长春碱和放线菌素D的特异性耐药谱分析显示，这三种异构体的耐药模式有重叠但又有明显区别。虽然所有三种P-gps赋予的长春碱耐药水平差异不超过2.5倍，但每种异构体可通过其赋予秋水仙碱和放线菌素D耐药的能力清楚区分。同样，对结构相关和不相关的P-gp调节剂的研究表明，在相应的mdr转染细胞中，各个调节剂消除长春碱耐药的能力存在强烈的异构体特异性差异。对几种二取代哌嗪类似物的研究表明，该调节剂连接区的微小化学修饰对每种异构体对该调节剂的敏感性谱有强烈影响。总之，这些结果表明，所分析的三种P-gp异构体在与药物和调节剂相互作用方面具有特定且可区分的功能特征。这些发现还表明，在设计和体内测试用于逆转对表达人类MDR1的肿瘤细胞的多药耐药性的新型P-gp调节剂时，应谨慎使用P-gp阳性的小鼠可移植肿瘤。
