Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.5.1.3 (
dihydrofolate reductase
)
5,819
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The transfer of a drug resistance gene into hematopoietic cells is an approach being investigated to overcome the problem of myelosuppression produced by anticancer drugs. Chemotherapeutic agents are often given in combination in order to increase their effectiveness. Consequently, there is an advantage in designing vectors for gene transfer that are capable of expressing two drug resistance genes. We have constructed a bicistronic retroviral vector, MFG-
DHFR
-IRES/CD, which contains the mutated human
dihydrofolate reductase
(
DHFR
) cDNA with a phenylalanine-to-serine substitution at codon 31 (F31S) and the human cytidine deaminase (CD) cDNA. Murine fibroblast and hematopoietic cells were transduced with this vector and evaluated for their resistance to methotrexate (MTX) and cytosine arabinoside (
ARA-C
). The transduced fibroblast cells showed high levels of resistance to MTX and to
ARA-C
as determined by a clonogenic assay. Using enzymatic assays, we observed a coordinate increase in resistance to MTX and
DHFR
enzyme activity following an
ARA-C
selection. In addition, MTX selection produced an increase in CD enzyme activity and
ARA-C
resistance. Murine hematopoietic cells transduced with the bicistronic vector also showed drug resistance to both MTX and
ARA-C
. Interestingly, the double-gene construct conferred an equivalent level of drug resistance compared with single-gene vectors bearing only CD or
DHFR
genes in the hematopoietic cells. These results demonstrate the potential of the MFG-
DHFR
-IRES/CD vector to confer drug resistance to both MTX and
ARA-C
and may have future application in chemoprotection of normal hematopoietic cells in patients with cancer.
...
PMID:Coexpression of cytidine deaminase and mutant dihydrofolate reductase by a bicistronic retroviral vector confers resistance to cytosine arabinoside and methotrexate. 985 20
