TREATMENT OF MULTIDRUG-RESISTANT MURINE LEUKEMIA WITH ANTISENSE MDR1 OLIGODEOXYNUCLEOTIDES

To overcome multidrug resistance in a P-glycoprotein-overexpressing. P 388/ADR murine leukemia cell line, antisense mdrl phosphorothioate-oli godeoxynucleotide (AS-oligomer) was constructed. AS-oligomer inhibited P-glycoprotein expression and mdrl mRNA in vitro in a dose-dependent manner, whereas sense mdrl oligomer (SE-oligomer) had no effect at the doses used. When P388/ADR was treated in vitro with AS-oligomer and d oxorubicin (ADR), ADR-resistance was reduced by approximately 2 logs. Furthermore, a single injection of AS-oligomer plus ADR intraperitonea lly into B6D2F1 mice with P388/ADR significantly prolonged mean surviv al time in a dose-dependent fashion. Again, sense mdrl 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 mdrl oligomer could be a useful tool to overcome multid rug resistance.