Annals of Surgical Oncology

, Volume 3, Issue 1, pp 80–85 | Cite as

Modulation of multidrug resistance with antisense oligodeoxynucleotide to mdr1 mRNA

  • Juan E. Sola
  • Paul M. Colombani
Original Articles

Abstract

Background: P-glycoprotein (Pgp), a 170-kDa adenosine triphosphate-dependent membrane drug-efflux pump encoded by themdr1 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 oligodeoxynucleotide complementary to the initiation codon ofmdr1 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.

Key Words

Antisense Chemoresistance P-glycoprotein Oligodeoxynucleotides 17F9 

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Copyright information

© The Society of Surgical Oncology, Inc 1996

Authors and Affiliations

  • Juan E. Sola
    • 1
  • Paul M. Colombani
    • 1
  1. 1.From the Division of Pediatric Surgery, Department of SurgeryThe Johns Hopkins UniversityBaltimoreUSA

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