MULTIDRUG-RESISTANCE AND THE ROLE OF P-GLYCOPROTEIN KNOCKOUT MICE

Drug resistance, be it intrinsic or acquired, is a major problem in ca ncer chemotherapy. In vitro, one well characterised form of resistance against many different cytotoxic drugs is caused by the MDR1 P-glycop rotein, a large plasma membrane protein that protects the cell by acti vely pumping substrate drugs out. Available evidence suggests that thi s protein may cause drug resistance in at least some clinical tumours. Drugs inhibiting the MDR1 P-glycoprotein activity are, therefore, co- administered during chemotherapy of these tumours. To predict the biol ogical and pharmacological effects of the blocking of this protein, we have generated mice with a genetic disruption of the drug-transportin g mdr1a P-glycoprotein. These mice are overall healthy, but they accum ulate much higher levels of substrate drugs in the brain, and have mar kedly slower elimination of these drugs from the circulation. For some drugs, this leads to dramatically increased toxicity, indicating that P-glycoprotein inhibitors should be used with caution in patients.