Vincristine degradation by serum from leukemic patients: role of myeloperoxidase.
Myeloperoxidase (MPO) has been shown to catalyze the in vitro degradation of vincristine (VCR). Given that MPO is a lysosomal enzyme that can be released into the circulation by both normal activated and leukemic myeloid cells, we investigated the possibility that sera from patients with acute myeloblastic leukemia (AML) might exhibit an increased capacity to degrade VCR. 31 serum samples (23 from patients with acute myeloblastic leukemia and 8 from patients with other conditions) were analyzed after incubation with ((3)H)VCR by using HPLC. Sera from patients with AML demonstrated an increased ability to breakdown VCR when compared to either normal sera or to sera from patients with lymphoid leukemias. VCR degradation was significantly increased by adding hydrogen peroxide, an electron donor for MPO, to the sera and was almost completely inhibited by adding 1 mM acetaminophen, an inhibitor of MPO. VCR peroxidation in the presence of hydrogen peroxide correlated both with the number of leukemic blasts in the circulation at the time the sera were obtained and with serum MPO concentrations determined by an immunoassay. These data suggest that the inactivity of VCR in AML may be due in part to its rapid peroxidation to inactive species by the MPO of leukemic myeloblasts.
Schlaifer
D
D
Service d'Hematologie, Clinique Dieulafoy, Hopital de Purpan, Toulouse, France.
Duchayne
E
E
Demur
C
C
Alvinerie
P
P
Muller
C
C
Attal
M
M
Cooper
M R
MR
Payen
C
C
Monsarrat
B
B
Myers
C E
CE
Pris
J
J
Laurent
G
G
D000082:Acetaminophen / Q000494:pharmacology; D000208:Acute Disease; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008658:Inactivation, Metabolic; D007951:Leukemia, Myeloid / Q000097:blood / Q000201:enzymology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000097:blood*; D014411:Neoplastic Stem Cells / Q000201:enzymology; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000097:blood*; D014750:Vincristine / Q000493:pharmacokinetics*
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D000082:Acetaminophen; D014750:Vincristine; D006861:Hydrogen Peroxide; D009195:Peroxidase