ANTISENSE INHIBITION OF MYELOPEROXIDASE INCREASES THE SENSITIVITY OF THE HL-60 CELL-LINE TO VINCRISTINE

Myeloperoxidase (MPO), a heme-peroxidase found in the HL-60 myeloblast ic cell line, is involved in vincristine (VCR) metabolism and the inac tivation of this drug. We have examined whether decreased MPO activity correlated with increased sensitivity to VCR toxicity in myeloid leuk emia cells. We have used MPO antisense RNA to reduce 60% of the MPO ac tivity in the HL-60 cells. The MPO-deficient HL-60 cell line, C15, was significantly more sensitive to VCR than the parental MPO-positive ce ll line. Both cell lines were negative for P170-glycoprotein expressio n. Conversely, an MPO-positive C15 subclone was more resistant to VCR than the MPO-deficient C15 cell line. No significant differences in cy totoxic effects were observed between MPO-positive and MPO-deficient c ells, following treatment with either daunorubicin or actinomycin D, t wo multidrug resistance-related drugs. These results strongly support an important role for MPO in VCR resistance in HL-60 cells. Antisense manipulation of the MPO content of myeloid cells could be of potential interest in leukemia treatment.