Treatment of multidrug-resistant murine leukemia with antisense mdr1 oligodeoxynucleotides

To overcome multidrug resistance in a P-glycoprotein-overexpressing P388/ADR murine leukemia cell line, antisense mdr1 phosphorothioate-oligodeoxynucleotide (AS-oligomer) was constructed. AS-oligomer inhibited P-glycoprotein expression and mdr1 mRNA in vitro in a dose-dependent manner, whereas sense mdr1 oligomer (SE-oligomer) had no effect at the doses used. When P388/ADR was treated in vitro with AS-oligomer and doxorubicin (ADR), ADR-resistance was reduced by approximately 2 logs. Furthermore, a single injection of AS-oligomer plus ADR intraperitoneally into B6D2F1 mice with P388/ADR significantly prolonged mean survival time in a dose-dependent fashion. Again, sense mdr1 oligomer had no effect in vivo. No side effects, either acute or chronic, were found with this treatment during the observation period. These results show that antisense mdr1 oligomer could be a useful tool to overcome multidrug resistance.