Effect of unmodified triple helix‐forming oligodeoxyribonucleotide targeted to human multidrug‐resistance gene mdr1 in MDR cancer cells

Abstract

The human mdrl gene encodes a transmembrane glycoprotein the over-expression of which is associated with development of multidrug resistance in human tumor cells. A negative modulation of human mdrt has been attempted via a 27-met unmodified triple helix-forming oligonucleotide, named 1 D, targeted to a homopurine sequence in the coding region of the gene. By administering 10/zM of 1D we could find a significant reduction in MDR1 mRNA levels in the human drug-resistant cell line CEM-VLBI00. This effect appears to be specific and due to a transient block of RNA polymerase mediated by triple helix formation.

Inhibition of aromatase expression by a psoralen‐linked triplex‐forming oligonucleotide targeted to a coding sequence

“…Because the transcribed region of a gene is generally much larger than the regulatory sequences, the ability to target coding sequences would increase the range of potential targets. Thus far this has been reported in a cell-free system [11], and in two studies in intact cells, targeting the fl-galactosidase and mdrl genes [12,13].…”

Modulation of the typical multidrug resistance phenotype by targeting the MED-1 region of human MDR1 promoter

“…20,21 The use of several antisense ODNs to modulate the MDR phenotype has already been reported: 15mer to 28mer ODNs have been used by different laboratories to target full-length human MDR1 cDNA. [22][23][24][25][26][27] Several methods have been developed to introduce ODNs into target cells. Viral vectors are rather efficient tools but may present safety risks; furthermore, their capacity is limited and large-scale production may be difficult to achieve.…”

Reversal of drug resistance of hepatocellular carcinoma cells by adenoviral delivery of anti-MDR1 ribozymes

“…Chemosensitization could also be seen after transfection of pancreatic, ovarian, and small-cell lung carcinoma cells with an expression vector coding for a hammerhead ribozyme targeted to cleave between the 2 ATP binding sites of the MDR1 mRNA (codon 880). 37 The possibility of exogenously modulating gene expression by intermolecular triplex formation has also been applied in vitro to chemosensitize MDR1 cells 38 via a 27-mer unmodified oligonucleotide targeted to a homopurinic stretch in exon 3 of the MDR1 coding region (position 69 to 93). A significant, specific, and dose-dependent reduction of MDR1 mRNA levels was observed in the treated drug resistant cell line CEM-VLB100.…”