Effect of anti-sense P-glycoprotein oligomer on P-glycoprotein-positive multidrug-resistant cancers

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Multidrug resistance (mdr) genes encode P-glycoprotein (P-gp), an active transporter that pumps cytotoxic drugs out of cells. Thus, its overexpression is associated with the anticancer drug resistance. Disrupting P-gp/mdr function might, therefore, form the basis of a strategy for overcoming the multidrug resistance of cancer cells. To overcome multidrug resistance in a P-gp-overexpressing P388/ADR murine leukemia cell line, antisense mdrl phosphorothioate-oligodeoxynucleotide (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 doxorubicin (ADR), ADR-resistance was reduced by approximately 2 logs. Furthermore, a single injection of AS-oligomer plus ADR intraperitoneally into B6D2 F1 mice with P388/ADR significantly prolonged mean survival time in a dose-dependent fashion. Again, sense mdrl oligomer had no effect in vivo. No side eddects, 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 multidrug resistance.