Modulation of multidrug resistance with antisense oligodeoxynucleotide to mdr1 mRNA

Juan E. Sola, Paul M. Colombani

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Background: P-glycoprotein (Pgp), a 170-kDa adenosine triphosphate-dependent membrane drug-efflux pump encoded by the mdr1 gene, mediates cross-resistance in tumor cells to structurally unrelated cancer drugs. We investigated the capacity for modulating multidrug resistance by selectively inhibiting synthesis of Pgp using an antisense oligodeoxy-nucleotide complementary to the initiation codon of mdr1 messenger RNA. Methods: By continuous culture of K562 in 100 nM vincristine, a resistant cell line, K562/VCR100, was derived with high expression of Pgp (95.9% of cells) and an IC50 40-fold greater than that of the parental cell line. The K562/VCR100 cells were treated with 10 μM of 15-mer antisense and sense phosphorothioate oligodeoxynucleotides. Modulation of multidrug resistance was analyzed using a daunorubicin/tritiated thymidine incorporation assay and flow cytometric assessment of cellular rhodamine 123 accumulation. Results: Treatment of K562/VCR100 with the antisense oligodeoxynucleotide led to a doubling in daunorubicin growth inhibition at 1 μg/ml and a tripling of growth inhibition at 0.6 μg/ml (p < 0.0023); a 58% reduction in the daunorubicin IC50 (p < 0.02); and an increased rate of rhodamine-123 accumulation (p = 0.02) compared with treatment with sense oligodeoxynucleotide or media controls. Conclusions: These results suggest that antisense oligodeoxynucleotides may serve as a useful adjunct in the treatment and prevention of multidrug resistance during cancer chamotherapy.

Original languageEnglish (US)
Pages (from-to)80-85
Number of pages6
JournalAnnals of Surgical Oncology
Volume3
Issue number1
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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Keywords

  • 17F9
  • Antisense
  • Chemoresistance
  • Oligodeoxynucleotides
  • P-glycoprotein

ASJC Scopus subject areas

  • Surgery
  • Oncology

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