In vitro and in vivo reversal of multidrug resistance in a human leukemia-resistant cell line by mdr1 antisense oligodeoxynucleotides

A major obstacle to successful cancer chemotherapy is the development of multidrug resistance (MDR) by tumor cells. Overexpression of the mdr1 gene product P-glycoprotein (P-170) is characteristic of such cells. In this study, in vitro and in vivo reversion of MDR was attempted in a human leukemia cell line resistant to vincristine (HL-60/Vinc) using an 18-mer mdr1 antisense phosphorothioate oligodeoxynucleotide ([S]ODN) in combination with vincristine. As control of sequence specificity, both sense and scrambled [S]ODNs were used. The ability of these [S]ODNs to reverse MDR was studied in vitro and in severe combined immunodeficient (SCID) mice. In vitro treatment with antisense [S]ODNs restored vincristine sensitivity of HL-60/Vinc cells, whereas no changes in drug sensitivity were observed upon treatment with the sense or scrambled sequence. The in vitro effects correlated with inhibition of P-170 expression in HL-60/Vinc cells exposed to the mdr1 antisense [S]ODNs. In vivo reversal of MDR was obtained in SCID mice given injections of HL-60/ Vinc cells and systemically treated with [S]ODNs plus vincristine, as indicated by a significantly prolonged survival of SCID mice that received the combination therapy of mdr1 antisense [S]ODNs + vincristine. Treatments with mdr1 antisense or scrambled [S]ODNs, vincristine, or scrambled [S]ODNs + vincristine had no effect on survival. These results suggest that the use of mdr1 antisense ODNs in combination with standard antineoplastic drugs might be useful in reversing MDR in vitro and in vivo.