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Multidrug resistant transgenic mice as a novel pharmacologic tool
G H Mickisch1, I Pastan, M M Gottesman
1Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Abstract:
Multidrug resistance resulting from expression of an energy-dependent drug efflux pump encoded by the human MDR1 gene is a major impediment to effective cancer therapy. Pharmacologic intervention aimed at inhibiting this multidrug transporter should improve existing chemotherapy of human cancer, but drug development has been delayed by the difficulty and expense of developing valid animal models. Using recombinant DNA technology, a transgenic mouse has been engineered whose bone marrow is protected from the toxic effects of chemotherapy by expression of the MDR1 gene. This animal system allows the rapid screening of drugs which inhibit the multidrug transporter and heralds a new era of using transgenic animals for pharmacologic screening.
Insights
Scientists engineered a transgenic mouse to combat multidrug resistance in cancer therapy. This new animal model enables rapid drug screening to inhibit the multidrug transporter, improving chemotherapy effectiveness.
Area of Science:
- Biotechnology
- Pharmacology
- Oncology
Background:
- Multidrug resistance (MDR) in cancer is often mediated by efflux pumps like the one encoded by the human MDR1 gene.
- This resistance significantly hinders the efficacy of conventional chemotherapy.
- Developing effective animal models for studying MDR and screening inhibitors has been challenging and costly.
Purpose of the Study:
- To develop a novel transgenic animal model for studying multidrug resistance in cancer.
- To facilitate the rapid screening of pharmacologic agents that inhibit multidrug transporters.
- To overcome limitations associated with current animal models in drug development for cancer therapy.
Main Methods:
- Utilized recombinant DNA technology to create a transgenic mouse model.
- Engineered the mouse to express the human MDR1 gene.
- The expression of MDR1 in bone marrow confers protection against chemotherapy toxicity.
Main Results:
- Successfully generated a transgenic mouse model expressing the MDR1 gene.
- Demonstrated that bone marrow in these mice is protected from chemotherapy's toxic effects.
- Established a system for the rapid screening of drugs targeting multidrug transporters.
Conclusions:
- The developed transgenic mouse model offers a valuable platform for pharmacologic screening.
- This innovation represents a significant advancement in developing strategies to overcome multidrug resistance in cancer.
- Transgenic animal models are poised to revolutionize drug discovery and development in oncology.