HUMAN (MDR1) AND MOUSE (MDR1,MDR3) P-GLYCOPROTEINS CAN BE DISTINGUISHED BY THEIR RESPECTIVE DRUG-RESISTANCE PROFILES AND SENSITIVITY TO MODULATORS

Possible functional differences between P-glycoproteins (P-gps) encode d by the human MDR1 and mouse mdr1 and mdr3 genes with respect to drug resistance profiles and sensitivity to known modulators have been inv estigated. For this, the three genes were introduced and overexpressed in the same cellular background, that of Chinese hamster LR73 ovary c ells, and drug-resistant clones expressing comparable amounts of the c orresponding P-gps were selected under the same conditions. Analysis o f the specific drug resistance profiles encoded by each P-gp for colch icine, adriamycin, vinblastine, and actinomycin D revealed overlapping but distinct patterns of drug resistance for the three isoforms. Whil e all three P-gps conferred levels of resistance to vinblastine that d id not vary by more than 2.5-fold, each isoform could be clearly disti nguished by its capacity to confer resistance to colchicine and actino mycin D. Likewise, the study of structurally related and unrelated P-g p modulators indicated strong isoform-specific differences in the capa city of individual modulators to abrogate vinblastine resistance in th e 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 indi cate that the three P-gp isoforms analyzed have specific and distingui shable functional characteristics with respect to interactions with dr ugs and modulators. These findings also suggest that P-gp positive mur ine transplantable tumors should be used with caution in the design an d in vivo testing of novel P-gp modulators to be used to reverse multi drug resistance to tumor cells expressing human MDR1.