MODULATION OF MULTIDRUG-RESISTANCE WITH ANTISENSE OLIGODEOXYNUCLEOTIDE TO MDR1 MESSENGER-RNA

Background: P-glycoprotein (Pgp), a 170-kDa adenosine triphosphate-dep endent membrane drug-efflux pump encoded by the mdr1 gene, mediates cr oss-resistance in tumor cells to structurally unrelated cancer drugs. We investigated the capacity for modulating multidrug resistance by se lectively inhibiting synthesis of Pgp using an antisense oligodeoxynuc leotide complementary to the initiation codon of mdr1 messenger RNA. M ethods: By continuous culture of K562 in 100 nM vincristine, a resista nt cell line, K562/VCR(100), 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/VCR(100) cells were treated with 10 mu M of 15-mer antisense and sense phosphorothioate oligodeoxynucleotides. Modulatio n of multidrug resistance was analyzed using a daunorubicin/tritiated thymidine incorporation assay and flow cytometric assessment of cellul ar rhodamine 123 accumulation. Results: Treatment of K562/VCR(100) wit h the antisense oligodeoxynucleotide led to a doubling in daunorubicin growth inhibition at 1 mu g/ml and a tripling of growth inhibition at 0.6 mu g/ml (p < 0.0023); a 58% reduction in the daunorubicin IC50 (p < 0.02); and an increased rate of rhodamine-123 accumulation (p = 0.0 2) compared with treatment with sense oligodeoxynucleotide or media co ntrols. Conclusions: These results suggest that antisense oligodeoxynu cleotides may serve as a useful adjunct in the treatment and preventio n of multidrug resistance during cancer chamotherapy.