Potential strategies for circumventing myeloperoxidase-catalyzed degradation of vinca alkaloids.

Myeloperoxidase (MPO) has recently been shown in an in vitro, cell-free system to catalyze the peroxidative degradation of vincristine (VCR). Oxidation of VCR involves a ring fission between positions 20' and 21', and is thought to be facilitated by the presence of an hydroxyl (-OH) group at position 20'. We report here two different approaches, both with potential clinical application, to decrease MPO-catalyzed vinca degradation. Firstly, we tested the hypothesis that -OH substitution at position 20' increases vinca susceptibility to peroxidation by comparing the relative extent of degradation of vinorelbine (Navelbine or NVB), which lacks a 20' hydroxyl substitution, with that of VCR. As anticipated, NVB was significantly less susceptible to MPO-catalyzed peroxidation than was VCR (p < 0.01). Secondly, we screened an array of compounds that are in current clinical use for their ability to inhibit MPO. Acetaminophen, N-acetylcysteine, propylthiouracil, D-penicillamine, mefenamic acid, dapsone, and methimazole all inhibited MPO at clinically achievable concentrations. Insofar as increased MPO activity has been observed in patients with acute myeloid leukemia, these findings suggest potential strategies for improving the activity of vinca alkaloids in this disease.