Degradation of vincristine by myeloperoxidase and hypochlorous acid in

Abstract

Vincristine (VCR) is an effective drug against acute lymphoblastic leukemia (ALL), many solid tumors, but not acute myeloid leukemia. It has been hypothesized that resistance of myeloblasts to VCR is related to myeloperoxidase (MPO) and production of hypochlorous acid (HOCl). We investigated the relationship between VCR degradation and MPO expression and serum HOCl concentrations in pediatric patients with ALL, lymphoma and solid tumors. We studied the sera from 43 children, of which 23 were newly diagnosed and as yet untreated cancer patients, 10 on chemotherapy and 10 healthy control subjects. Patients' sera were incubated with VCR alone or in the presence of taurine (T) or acetaminophen (APAP) and post-incubation VCR and HOCL concentrations were measured. Significant correlations between serum MPO expression, HOCl concentrations and VCR degradation were seen. In the chemotherapy group, MPO-positive patients produced high levels of HOCl and reciprocally low post-incubation VCR levels. HOCl and VCR concentrations in this group were significantly different than other groups studied. Both APAP and T inhibited VCR degradation in the sera of the chemotherapy group but not to the same degree. The effects seen here were consistent for both ALL and the lymphoma/solid tumor cases. Our results indicate that HOCl can increase VCR degradation in vitro in the serum and this effect is significantly more pronounced in pediatric patients undergoing chemotherapy. (C) 2003 Elsevier Science Ltd. All rights reserved.

C1 Inonii Univ, Sch Med, Dept Pediat, Malatya, Turkey.

Inonii Univ, Sch Med, Dept Biochem, Malatya, Turkey.

Wayne State Univ, Childrens Hosp Michigan, Barbara Ann Karmanos Canc Inst, Div Hematol Oncol, Wayne, MI USA.