Expression of a human multidrug resistance cDNA (MDR1) in the bone marrow of transgenic mice: resistance to daunomycin-induced leukopenia.
The human multidrug resistance gene (MDR1) encodes a drug efflux pump glycoprotein (P-glycoprotein) responsible for resistance to multiple cytotoxic drugs. A plasmid carrying a human MDR1 cDNA under the control of a chicken beta-actin promoter was used to generate transgenic mice in which the transgene was mainly expressed in bone marrow and spleen. Immunofluorescence localization studies showed that P-glycoprotein was present on bone marrow cells. Furthermore, leukocyte counts of the transgenic mice treated with daunomycin did not fall, indicating that their bone marrow was resistant to the cytotoxic effect of the drug. Since bone marrow suppression is a major limitation to chemotherapy, these transgenic mice should serve as a model to determine whether higher doses of drugs can cure previously unresponsive cancers.
Galski
H
H
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
Sullivan
M
M
Willingham
M C
MC
Chin
K V
KV
Gottesman
M M
MM
Pastan
I
I
Merlino
G T
GT
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000199:Actins / Q000235:genetics; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D003630:Daunorubicin / Q000633:toxicity; D004351:Drug Resistance / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010957:Plasmids; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000199:Actins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D003630:Daunorubicin