Myeloperoxidase: an enzyme involved in intrinsic vincristine resistance in human myeloblastic leukemia.
One of the differences between acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL) is their sensitivity to vincristine. Although vincristine plays an important role in chemotherapeutic regimens for ALL, it does not possess clinically significant activity in AML. Horseradish peroxidase, a heme-centered peroxidase, oxidatively degrades Vinca derivatives and thereby abrogates their cytotoxic activity. This finding suggested that myeloperoxidase (MPO), a heme-centered peroxidase characteristically found in AML and not in ALL, might also degrade vincristine. We first examined the effects of MPO on vincristine in a cell-free system and demonstrated that this enzyme is capable of catalyzing vincristine's oxidative breakdown. We also observed that vincristine is more rapidly degraded in tissue culture by MPO-positive HL-60 cells than by a MPO-negative HL-60 subclone. The degree of MPO activity in these cell lines correlated in a positive manner with their degree of resistance to vincristine's cytotoxic activity. Moreover, the differential resistance to vincristine observed between these cell lines could be increased by increasing the concentration of H2O2 available to the enzyme. These data support the hypothesis that MPO-mediated oxidation of vincristine accounts in part for this drug's lack of activity in AML.
Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
D
D
Schlaifer
M R
MR
Cooper
M
M
Attal
A O
AO
Sartor
J B
JB
Trepel
G
G
Laurent
C E
CE
Myers
D000954:Antigens, Surface / Q000032:analysis; D003594:Cytoplasmic Granules / Q000201:enzymology* / Q000648:ultrastructure; D004351:Drug Resistance / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism*; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000378:metabolism* / Q000494:pharmacology*
D000954:Antigens, Surface; D014750:Vincristine; D009195:Peroxidase