Expression of a human complementary DNA for the multidrug resistance gene in murine hematopoietic precursor cells with the use of retroviral gene transfer.
In multidrug resistance, cells become simultaneously resistant to anthracyclines, vinca alkaloids, epipodophyllotoxins, and certain other natural product cytotoxic drugs. Resistance results from synthesis of a multidrug transporter (P-glycoprotein) encoded by the MDR1 gene (also known as the PGY1 gene). In the present study, a retrovirus vector containing a complementary DNA for the human multidrug resistance gene HaMDR1/A was used to transfer the multidrug resistance phenotype to bone marrow cells of the DBA/2J mouse. A high proportion of transduced bone marrow cells showed resistance to both colchicine and vinblastine, as determined by in vitro colony formation of hematopoietic precursor cells. In addition, brief culturing of the cells in a cytotoxic drug following exposure to the retrovirus vector could be used to increase the proportion of bone marrow cell colonies that were resistant. These results may serve as a model for the generation and selection of bone marrow cells resistant to the toxic effects of chemotherapeutic agents in vivo.
McLachlin
J R
JR
Laboratory of Molecular Hematology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Eglitis
M A
MA
Ueda
K
K
Kantoff
P W
PW
Pastan
I H
IH
Anderson
W F
WF
Gottesman
M M
MM
D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D002999:Clone Cells / Q000502:physiology; D003078:Colchicine / Q000494:pharmacology; D004247:DNA / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D015870:Gene Expression / Q000502:physiology*; D005814:Genes, Viral / Q000502:physiology; D006251:Harvey murine sarcoma virus / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008747:Methylcellulose; D051379:Mice; D010641:Phenotype; D012190:Retroviridae / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology; D014161:Transduction, Genetic / Q000502:physiology; D014162:Transfection / Q000235:genetics*
D008747:Methylcellulose; D004247:DNA; D003078:Colchicine