RT Journal Article
SR Electronic
T1 Effect of methotrexate on dihydrofolate reductase activity in methotrexate-resistant human KB cells.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 478
OP 482
VO 21
IS 2
A1 B A Domin
A1 S P Grill
A1 K F Bastow
A1 Y C Cheng
YR 1982
UL http://molpharm.aspetjournals.org/content/21/2/478.abstract
AB A cloned subline of human cell variants derived from KB cells (KB/6b), 6500-fold resistant to methotrexate (MTX), exhibited a stable 40-fold elevation of the enzyme dihydrofolate reductase (EC 1.5.1.3., DHFR) in the absence of the drug. No differences were detected between the enzyme isolated from resistant and parental KB cells. After the culture medium was supplemented with MTX, the resistant cells were shown to have an additional 5-fold increase in DHFR levels. This increment was dependent upon the concentration of exogenous MTX and was freely reversible. This behavior differs from that of other DHFR-overproducing mammalian cell lines previously reported. The half-life of DHFR in these cells in the presence or absence of MTX was the same, thus eliminating stabilization of the enzyme by MTX as being responsible for the modulation or "induction" phenomenon. Furthermore, the effect was blocked by cycloheximide and was not affected by actinomycin D. These results suggest that modulation of DHFR specific activity by MTX occurs at either the translational level or by as yet undefined post-transcriptional mechanism(s).