Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT01586 (G418)
 2,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to reverse P-glycoprotein-mediated drug resistance in a specific manner, we designed two hammerhead ribozymes which can cleave the GUC sequence in codon 179 and 196 of MDR1 (PGY1) mRNA. The ribozymes were directly synthesized using a set of primers, one containing a bacteriophage T7 RNA polymerase promoter. A target MDR1 RNA was created by a reverse transcription polymerase chain reaction using a MOLT-3 human acute leukemia cell line resistant to trimetrexate (TMQ) (MOLT-3/TMQ800), which displayed MDR1 overexpression. In a cell-free system, both ribozymes cleaved a target piece of MDR1 RNA into 2 fragments at the specific sites at a physiological pH and temperature. The cleavage reaction was dependent on time, ribozyme:substrate ratio, and magnesium concentration. The 196 MDR1 ribozyme was more active than the 179 MDR1 ribozyme. The 196 MDR1 ribozyme was then cloned into a human expression vector, and MOLT-3/TMQ800 cells were transfected. The original MOLT-3/TMQ800 cells were nearly 700-fold resistant to vincristine, whereas the transfectant cells selected in G418 became only 20- to 30-fold resistant. The level of resistance and the amount of MDR1 RNA expressed appeared to correlate inversely with the amount of ribozyme expression. A disabled 196 MDR1 ribozyme was capable of neither specific cleavage in vitro nor decreasing MDR1 expression in transfectant cells. These results indicate that it was the ribozyme activity and not antisense activity which was responsible for decreased MDR1 RNA. This approach may be applicable to cancer patients as a specific means to reverse tumors with P-glycoprotein-mediated MDR phenotype back to a drug-sensitive one.
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PMID:Reversal of drug sensitivity in multidrug-resistant tumor cells by an MDR1 (PGY1) ribozyme. 811 16

The interaction of an exogenous PML/RAR alpha fusion gene associated with acute promyelocytic leukaemia, with all-trans retinoic acid (ATRA) was examined in two lymphoid cell lines. L1210 and MOLT-4 cells were transfected with PML/RAR alpha cDNA in the expression vector pGD and stable transformants (L1210PML/RAR alpha and MOLT-4PML/RAR alpha) were selected with G418. ATRA inhibited the growth of these stable transformants, as assessed by [3H]thymidine incorporation, in a dose-dependent manner, but had no effect on the growth of control cells stably transformed with neomycin resistant gene alone. ATRA also induced apoptosis, as assessed by fragmentation of genomic DNA, in L121OPML/RAR alpha and MOLT-4PML/RAR alpha cells but not in control cells. The exogenous PML/RAR alpha fusion gene therefore probably mediates the effects of ATRA on cell growth and apoptosis in these cell lines.
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PMID:Inhibition of growth and induction of apoptosis by all-trans retinoic acid in lymphoid cell lines transfected with the PML/RAR alpha fusion gene. 870 36