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Multidrug resistance and the role of P-glycoprotein knockout mice
A H Schinkel1, C A Mol, E Wagenaar
1The Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam, The Netherlands.
Abstract:
Drug resistance, be it intrinsic or acquired, is a major problem in cancer chemotherapy. In vitro, one well characterised form of resistance against many different cytotoxic drugs is caused by the MDR1 P-glycoprotein, a large plasma membrane protein that protects the cell by actively pumping substrate drugs out. Available evidence suggests that this 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 biological and pharmacological effects of the blocking of this protein, we have generated mice with a genetic disruption of the drug-transporting mdr1a P-glycoprotein. These mice are overall healthy, but they accumulate much higher levels of substrate drugs in the brain, and have markedly 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.
Insights
Drug resistance in cancer chemotherapy is a major challenge. Blocking the MDR1 P-glycoprotein in mice increased drug accumulation in the brain and toxicity, suggesting caution with P-glycoprotein inhibitors in patients.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Drug resistance is a significant obstacle in cancer chemotherapy.
- The MDR1 P-glycoprotein actively transports cytotoxic drugs out of cells, contributing to resistance.
- P-glycoprotein inhibitors are co-administered to overcome drug resistance in clinical settings.
Purpose of the Study:
- To investigate the biological and pharmacological consequences of blocking P-glycoprotein activity.
- To generate and characterize genetically modified mice lacking the mdr1a P-glycoprotein.
Main Methods:
- Generation of mice with a genetic disruption of the drug-transporting mdr1a P-glycoprotein.
- Assessment of drug accumulation in the brain and elimination from circulation in these mice.
- Evaluation of drug toxicity in the genetically modified mouse model.
Main Results:
- Mice lacking mdr1a P-glycoprotein exhibited significantly higher drug levels in the brain.
- These mice showed markedly slower elimination of substrate drugs from their circulation.
- Certain drugs demonstrated dramatically increased toxicity in the genetically modified mice.
Conclusions:
- Genetic disruption of mdr1a P-glycoprotein leads to altered drug pharmacokinetics and increased toxicity.
- The findings highlight the critical role of P-glycoprotein in drug disposition and toxicity.
- P-glycoprotein inhibitors should be administered with caution in cancer patients due to potential toxicity.