Advances in Brief In Vitro and in Vivo Reversal of Multidrug Resistance in a Human Leukemia- resistant Cell Line by mdrl Antisense Oligodeoxynucleotides1

A major obstacle to successful cancer chemotherapy is the dtvelopment of multidrug resistance (MDR) by tumor cells. Overexpression of the mdrl gene product I'-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 mdrl antisense phosphorothioate oligodeoxynucleotide i|S]OI>\ i in com bination 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]()DNs restored vincristine sensitivity of HL-60A'inc 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 expres sion in HL-ftOA'inc cells exposed to the mdrl antisense |S]ODNs. In vivo reversal of MDR was obtained in SCIO mice given injections of HL-60/ Vine cells and systemically treated with [SjODNs plus vincristine, as indicated by a significantly prolonged survival of SCID mice that received the combination therapy of mdrl antisense |S)ODNs + vincristine. Treat ments with mdrl antisense or scrambled [S]ODNs, vincristine, or scram bled |S|ODNs + vincristine had no effect on survival. These results suggest that the use of mdrl antisense ODNs in combination with standard antineoplastic drugs might be useful in reversing MDR in vitro and in vivo.