Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance
- National Institutes of Health, Bethesda, MD (United States)
The development of preclinical models for the rapid testing of agents that circumvent multidrug resistance in cancer is a high priority of research on drug resistance. A common form of multidrug resistance in human cancer results from expression of the MDR1 gene, which encodes a M{sub r} 170,000 glycoprotein that functions as a plasma membrane energy-dependent multidrug efflux pump. The authors have engineered transgenic mice that express this multidrug transporter in their bone marrow and demonstrated that these animals are resistant to leukopenia by a panel of anticancer drugs including anthracyclines, vinca alkaloids, etoposide, taxol, and actinomycin D. Differential leukocyte counts indicate that both neutrophils and lympohcytes are pretected. Drugs such as cisplatin, methotrexate, and 5-fluorouracil, which are not handled by the multidrug transporter, produce bone marrow suppression in both normal and transgenic mice. The resistance conferred by the MDR1 gene can be circumvented in a dose-dependent manner by simultaneous administration of agents previously shown to be inhibitors of the multidrug transporter in vitro, including verapamil isomers, quinidine, and quinine. They conclude that MDR1-transgenic mice provide a rapid and reliable system to determine the bioactivity of agents that reverse multidrug resistance in animals.
- OSTI ID:
- 5074247
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America; (United States), Vol. 88:2; ISSN 0027-8424
- Country of Publication:
- United States
- Language:
- English
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BONE MARROW CELLS
SENSITIVITY
GLYCOPROTEINS
GENE REGULATION
ALKALOIDS
CHEMOTHERAPY
DOSE-RESPONSE RELATIONSHIPS
FLUOROURACILS
GENES
HEMATOLOGIC AGENTS
LEUKOCYTES
MAN
METHOTREXATE
MICE
NEOPLASMS
NEUTROPHILS
PLATINUM COMPOUNDS
ANIMAL CELLS
ANIMALS
ANTIMETABOLITES
AZINES
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CONNECTIVE TISSUE CELLS
DISEASES
DRUGS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
MAMMALS
MATERIALS
ORGANIC COMPOUNDS
ORGANIC FLUORINE COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PRIMATES
PROTEINS
PYRIMIDINES
RODENTS
SOMATIC CELLS
THERAPY
TRANSITION ELEMENT COMPOUNDS
URACILS
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology