REVERSAL OF DRUG-SENSITIVITY IN MDR SUBLINE OF P388 LEUKEMIA BY GENE-TARGETED ANTISENSE OLIGONUCLEOTIDE

We attempted to reverse multidrug resistance (MDR) by treatment with 2 5-mer antisense phosphorothioate oligonucleotide. The phosphorothioate analogs, the sequences of which are sense or antisense to the initiat ion codon of mouse mdrl mRNA, were tested against murine leukemic P388 /S and adriamycin-resistant P388/ADR cell lines. A weak inhibitory eff ect on the growth of P388/S and P388/ADR cells was observed at a sense and antisense oligonucleotide concentration of 30 mu M. Using the mon oclonal antibody to beta-glycoprotein and a flow cytometry technique, we showed that the level of expression of beta-glycoprotein in P388/AD R cells treated with antisense oligonucleotide was lower than when tre ated with sense oligonucleotide. The antisense oligonucleotide potenti ated the growth-inhibitory effect of vinblastine on P388/ADR cells, wh ereas sense oligonucleotide did not. This was accompanied by an increa se in vinblastine retention in the cells. The reversal of the resistan ce by antisense oligonucleotide was increased by the combination with 1 mu M verapamil. These results suggest that the antisense oligonucleo tide and low dose verapamil may be useful in circumventing the resista nce to anticancer drugs of MDR tumors.